Substituted pyrroline kinase inhibitors

ABSTRACT

The present invention is directed to novel substituted pyrroline compounds useful as kinase inhibitors and methods for treating or ameliorating a kinase mediated disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional patent application Ser.No. 60/378,503, filed on May 8, 2002, which is hereby incorporated byreference herein.

FIELD OF THE INVENTION

This invention is directed to certain novel compounds, methods forproducing them and methods for treating or ameliorating a kinasemediated disorder. More particularly, this invention is directed tosubstituted pyrroline compounds useful as selective kinase inhibitors,methods for producing such compounds and methods for treating orameliorating a kinase mediated disorder.

BACKGROUND OF THE INVENTION

Patent application WO 00/38675 discloses disubstituted maleimidecompounds of Formula compounds as GSK-3 (glycogen synthase kinase-3)inhibitors of Formula (A), (B) and (C):

wherein, for Formula (A), R is hydrogen; R² is hydrogen, 5-O-n-Pr, 5-Ph,5-CO₂Me or 5-NO₂; R³ is Me or (CH₂)₃OH, and; R⁴ is Me, n-Pr, —(CH₂)₃X,wherein X is selected from CN, NH₂, CO₂H, CONH₂ or OH; and, wherein, forFormula (B), R is hydrogen; R² is hydrogen; R³ is Me or a group—(CH₂)₃Y, wherein Y is NH₂ or OH; and, R⁴ is 2-Cl or 2,4-di-Cl.

Patent application WO 00/21927 describes 3-amino-4-arymaleimidecompounds of Formula (I):

or a pharmaceutically acceptable derivative thereof, wherein: R ishydrogen, alkyl, aryl or aralkyl; R¹ is hydrogen, alkyl, aralkyl,hydroxyalkyl or alkoxyalkyl; R² is substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl; R³ is hydrogen, substitutedor unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkylwherein the aryl moiety is substituted or unsubstituted; or, R¹ and R³together with the nitrogen to which they are attached form a single orfused, optionally substituted, saturated or unsaturated heterocyclicring and a method for the treatment of conditions associated with a needfor inhibition of GSK-3, such as diabetes, dementias such as Alzheimer'sdisease and manic depression.

U.S. Pat. No. 5,057,614 to Davis, et. al., describes substituted pyrrolecompounds of formula (I):

wherein R¹ signifies hydrogen, alkyl, aryl (limited to phenyl), aralkyl(limited to phenylalkyl), alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl,aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl,isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl,arylthioalkyl or carboxyalkylthioalkyl or a group of the formula—(CH₂)_(n)—W-Het (a), —(CH₂)_(n)-T-C(═V)-Z (b),—(CH₂)_(n)—NH—C(═O)-Im (c), or —(CH₂)_(n)—NH—C(═NH)—Ar (d)in which Het signifies a heterocyclyl group, W signifies NH, S or abond, T signifies NH or S, V signifies O, S, NH, NNO₂, NCN or CHNO₂, Zsignifies alkylthio, amino, monoalkylamino or dialkylamino, Im signifies1-imidazolyl, Ar signifies aryl, and n stands for 2–6; R² signifieshydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,alkylthio or alkylsulphinyl; R³ signifies a carbocyclic or heterocyclicaromatic group; R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen,halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl oralkylsulphonyl; and one of X and Y signifies O and the other signifiesO, S, (H,OH) or (H,H); with the proviso that R¹ has a significancedifferent from hydrogen when R² signifies hydrogen, R³ signifies3-indolyl or 6-hydroxy-3-indolyl, R⁴, R⁵ and R⁷ each signify hydrogen,R⁶ signifies hydrogen or hydroxy and X and Y both signify O and when R²signifies hydrogen, R³ signifies 3-indolyl, R⁴, R⁵, R⁶ and R⁷ eachsignify hydrogen, X signifies (H,H) and Y signifies O; as well aspharmaceutically acceptable salts of acidic compounds of formula I withbases and of basic compounds of formula I with acids, as protein kinaseC inhibitors and as therapeutically active substances for the use incontrol or prevention of inflammatory, immunological, bronchopulmonaryand cardiovascular disorders.

An associated published paper (Davis, et. al., J. Med. Chem. 1992, 35,177–184), disclosed a compound of formula (I) wherein R⁴, R⁵, R⁶ and R⁷signify hydrogen; R¹ signifies methyl; X and Y signify O; and R³signifies 3-(7-aza-1-methylindolyl) as a protein kinase C inhibitor(IC₅₀=2.9 μM).

Patent application WO 95/07910 describes heterocyclylindole derivativesof formula (I):

as antiviral agents. Preparation of compounds of formula (I) include useof indolyl(7-azaindolyl)maleimide compounds andbis(7-azaindolyl)maleimide compounds as reaction intermediates.

The substituted pyrroline compounds of the present invention have notbeen heretofore disclosed.

Accordingly, it is an object of the present invention to providesubstituted pyrroline compounds useful as a kinase or dual-kinaseinhibitor (in particular, a kinase selected from protein kinase C orglycogen synthase kinase-3; and, more particularly, a kinase selectedfrom protein kinase C α, protein kinase C β-II, protein kinase C γ orglycogen synthase kinase-3β), methods for their production and methodsfor treating or ameliorating a kinase or dual-kinase mediated disorder.

SUMMARY OF THE INVENTION

The present invention is directed to substituted pyrroline compounds ofFormula (I):

wherein

-   R is selected from the group consisting of R_(a), —C₁₋₈alkyl-R_(a),    —C₂₋₈alkenyl-R_(a), —C₂₋₈alkynyl-R_(a) and cyano;-   R_(a) is selected from the group consisting of cycloalkyl,    heterocyclyl, aryl and heteroaryl;-   R¹ is selected from the group consisting of hydrogen, —C₁₋₈alkyl-R⁵,    —C₂₋₈alkenyl-R⁵, —C₂₋₈alkynyl-R⁵, —C(O)—(C₁₋₈)alkyl-R⁹,    —C(O)-aryl-R⁸, —C(O)—O—(C₁₋₈)alkyl-R⁹, —C(O)—O-aryl-R⁸,    —C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—NH(aryl-R⁸), —C(O)—N(C₁₋₈alkyl-R⁹)₂,    —SO₂—(C₁₋₈)alkyl-R⁹, —SO₂-aryl-R⁸, -cycloalkyl-R⁶, -heterocyclyl-R⁶,    -aryl-R⁶ and -heteroaryl-R⁶; wherein heterocyclyl and heteroaryl are    attached to the azaindole nitrogen atom in the one position via a    heterocyclyl or heteroaryl ring carbon atom;-   R⁵ is 1 to 2 substituents independently selected from the group    consisting of hydrogen, —O—(C₁₋₈)alkyl, —O-aryl-R⁶,    —O—(C₁₋₈)alkyl-OH, —O—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-NH₂,    —O—(C₁₋₈)alkyl-NH(C₁₋₈alkyl), —O—(C₁₋₈)alkyl-N(C₁₋₈alkyl)₂,    —O—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-SO₂—NH₂, —O—(C₁₋₈)alkyl-SO₂—NH(C₁₋₈alkyl),    —O—(C₁₋₈)alkyl-SO₂—N(C₁₋₈alkyl)₂, —O—C(O)H, —O—C(O)—(C₁₋₈)alkyl,    —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₈alkyl), —O—C(O)—N(C₁₋₈alkyl)₂,    —O—(C₁₋₈)alkyl-C(O)H, —O—(C₁₋₈)alkyl-C(O)—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-CO₂H, —O—(C₁₋₈)alkyl-C(O)—O—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-C(O)—NH₂, —O—(C₁₋₈)alkyl-C(O)—NH(C₁₋₈alkyl),    —O—(C₁₋₈)alkyl-C(O)—N(C₁₋₈alkyl)₂, —C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H,    —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C₁₋₈alkyl),    —C(O)—N(C₁₋₈alkyl)₂, —SH, —S—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-OH, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH₂,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH(C₁₋₈alkyl),    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-N(C₁₋₈alkyl)₂,    —S—(C₁₋₈)alkyl-NH(C₁₋₈alkyl), —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,    —SO₂—NH(C₁₋₈alkyl), —SO₂—N(C₁₋₈alkyl)₂, —N—R⁷, cyano, (halo)₁₋₃,    hydroxy, nitro, oxo, -cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and    -heteroaryl-R⁶;-   R⁶ is 1 to 4 substituents attached to a carbon or nitrogen atom    independently selected from the group consisting of hydrogen,    —C₁₋₈alkyl, —C₂₋₈alkenyl, —C₂₋₈alkynyl, —C(O)H, —C(O)—(C₁₋₈)alkyl,    —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂,    —C(O)—NH(C₁₋₈alkyl), —C(O)—N(C₁₋₈)alkyl)₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH(C₁₋₈alkyl), —SO₂—N(C₁₋₈alkyl)₂, —(C₁₋₈)alkyl-N—R⁷,    —(C₁₋₈)alkyl-(halo)₁₋₃, —(C₁₋₈)alkyl-OH, -aryl-R⁸,    —(C₁₋₈)alkyl-aryl-R⁸ and —(C₁₋₈)alkyl-heteroaryl-R⁸;-   with the proviso that, when R⁶ is attached to a carbon atom, R⁶ is    further selected from the group consisting of —C₁₋₈alkoxy,    —(C₁₋₈)alkoxy-(halo)₁₋₃, —SH, —S—(C₁₋₈)alkyl, —N—R⁷, cyano, halo,    hydroxy, nitro, oxo and -heteroaryl-R⁸;-   R⁷ is 2 substituents independently selected from the group    consisting of hydrogen, —C₁₋₈alkyl, —C₂₋₈alkenyl, —C₂₋₈alkynyl,    —(C₁₋₈)alkyl-OH, —(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-NH₂,    —(C₁₋₈)alkyl-NH(C₁₋₈alkyl), —(C₁₋₈)alkyl-N(C₁₋₈alkyl)₂,    —(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —C(O)H, —C(O)—(C₁₋₈)alkyl,    —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl),    —C(O)—N(C₁₋₈alkyl)₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₈alkyl),    —SO₂—N(C₁₋₈alkyl)₂, —C(N)—NH₂, -cycloalkyl-R⁸,    —(C₁₋₈)alkyl-heterocyclyl-R⁸, -aryl-R⁸, —(C₁₋₈)alkyl-aryl-R⁸ and    —(C₁₋₈)alkyl-heteroaryl-R⁸;-   R⁸ is 1 to 4 substituents attached to a carbon or nitrogen atom    independently selected from the group consisting of hydrogen,    —C₁₋₈alkyl, —(C₁₋₈)alkyl-(halo)₁₋₃ and —(C₁₋₈)alkyl-OH;-   with the proviso that, when R⁸ is attached to a carbon atom, R⁸ is    further selected from the group consisting of —C₁₋₈alkoxy, —NH₂,    —NH(C₁₋₈alkyl), —N(C₁₋₈alkyl)₂, cyano, halo,    —(C₁₋₈)alkoxy-(halo)₁₋₃, hydroxy and nitro;-   R⁹ is 1 to 2 substituents independently selected from the group    consisting of hydrogen, —C₁₋₈alkoxy, —NH₂, —NH(C₁₋₈alkyl),    —N(C₁₋₈alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro;-   R² is one substituent attached to a carbon or nitrogen atom selected    from the group consisting of hydrogen, —C₁₋₈alkyl-R⁵,    —C₂₋₈alkenyl-R⁵, —C₂₋₈alkynyl-R⁵, —C(O)H, —C(O)—(C₁₋₈)alkyl-R⁹,    —C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—N(C₁₋₈alkyl-R⁹)₂,    —C(O)—NH(aryl-R⁸), —C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸,    —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —CO₂H, —C(O)—O—(C₁₋₈)alkyl-R⁹,    —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₈)alkyl-R⁹, —SO₂-aryl-R⁸, -cycloalkyl-R⁶,    -aryl-R⁶ and —(C₁₋₈)alkyl-N—R⁷;-   with the proviso that, when R² is attached to a carbon atom, R² is    further selected from the group consisting of —C₁₋₈alkoxy-R⁵, —N—R⁷,    cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R⁶ and    -heteroaryl-R⁶;-   R³ is 1 to 3 substituents attached to a carbon atom independently    selected from the group consisting of hydrogen, —C₁₋₈alkyl-R¹⁰,    —C₂₋₈alkenyl-R¹⁰, —C₂₋₈alkynyl-R¹⁰, —C₁₋₈alkoxy-R¹⁰, —C(O)H,    —C(O)—(C₁₋₈)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl-R⁹),    —C(O)—N(C₁₋₈alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸,    —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H,    —C(O)—O—(C₁₋₈)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₈)alkyl-R⁹,    —SO₂-aryl-R⁸, —N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸,    -heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁸;-   R⁴ is 1 to 4 substituents attached to a carbon atom independently    selected from the group consisting of hydrogen, —C₁₋₈alkyl-R¹⁰,    —C₂₋₈alkenyl-R¹⁰, —C₂₋₈alkynyl-R¹⁰, —C₁₋₈alkoxy-R¹⁰, —C(O)H,    —C(O)—(C₁₋₈)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl-R⁹),    —C(O)—N(C₁₋₈alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸,    —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H,    —C(O)—O—(C₁₋₈)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SH, —S—(C₁₋₈)alkyl-R¹⁰,    —SO₂—(C₁₋₈)alkyl-R⁹, —SO₂-aryl-R⁸, —SO₂—NH₂, —SO₂—NH(C₁₋₈alkyl-R⁹),    —SO₂—N(C₁₋₈alkyl-R⁹)₂, —N—R⁷, cyano, halogen, hydroxy, nitro,    -cycloalkyl-R⁸, -heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁸;-   R¹⁰ is 1 to 2 substituents independently selected from the group    consisting of hydrogen, —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈alkyl)₂, cyano,    (halo)₁₋₃, hydroxy, nitro and oxo; and,-   Y and Z are independently selected from the group consisting of O,    S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and    the other is selected from the group consisting of O, S, (H,OH) and    (H,H);    and pharmaceutically acceptable salts thereof.

The present invention is directed to substituted pyrroline compoundsuseful as a selective kinase or dual-kinase inhibitor; in particular, akinase selected from protein kinase C or glycogen synthase kinase-3;and, more particularly, a kinase selected from protein kinase C α,protein kinase C β (e.g. protein kinase C β-I and protein kinase Cβ-II), protein kinase C γ or glycogen synthase kinase-3β.

The present invention is also directed to methods for producing theinstant substituted pyrroline compounds and pharmaceutical compositionsand medicaments thereof.

The present invention is further directed to methods for treating orameliorating a kinase mediated disorder. In particular, the method ofthe present invention is directed to treating or ameliorating a kinasemediated disorder such as, but not limited to, cardiovascular diseases,diabetes, diabetes-associated disorders, inflammatory diseases,immunological disorders, dermatological disorders, oncological disordersand CNS disorders.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R is selected from the group consisting of R_(a),—C₁₋₄alkyl-R_(a), —C₂₋₄alkenyl-R_(a), —C₂₋₄alkynyl-R_(a) and cyano.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R_(a) is selected from the group consisting ofheterocyclyl, aryl and heteroaryl.

More preferably, R_(a) is selected from the group consisting ofdihydro-pyranyl, phenyl, naphthyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, azaindolyl, indazolyl, benzofuryl, benzothienyl,dibenzofuryl and dibenzothienyl.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R¹ is selected from the group consisting ofhydrogen, —C₁₋₄alkyl-R⁵, —C₂₋₄alkenyl-R⁵, —C₂₋₄alkynyl-R⁵,—C(O)—(C₁₋₄)alkyl-R⁹, —C(O)-aryl-R⁸, —C(O)—O—(C₁₋₄)alkyl-R⁹,—C(O)—O-aryl-R⁸, —C(O)—NH(C₁₋₄alkyl-R⁹), —C(O)—NH(aryl-R⁸),—C(O)—N(C₁₋₄alkyl-R⁹)₂, —SO₂—(C₁₋₄)alkyl-R⁹, —SO₂-aryl-R⁸,-cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and -heteroaryl-R⁶; whereinheterocyclyl and heteroaryl are attached to the azaindole nitrogen atomin the one position via a heterocyclyl or heteroaryl ring carbon atom.

More preferably, R¹ is selected from the group consisting of hydrogen,—C₁₋₄alkyl-R⁵, -aryl-R⁶ and -heteroaryl-R⁶; wherein heteroaryl isattached to the azaindole nitrogen atom in the one position via aheteroaryl ring carbon atom.

Most preferably, R¹ is selected from the group consisting of hydrogen,—C₁₋₄alkyl-R⁵ and -naphthyl-R⁶.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R⁵ is 1 to 2 substituents independently selectedfrom the group consisting of hydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶,—O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-NH₂,—O—(C₁₋₄)alkyl-NH(C₁₋₄alkyl), —O—(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂,—O—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-SO₂—NH₂, —O—(C₁₋₄)alkyl-SO₂—NH(C₁₋₄alkyl),—O—(C₁₋₄)alkyl-SO₂—N(C₁₋₄alkyl)₂, —O—C(O)H, —O—C(O)—(C₁₋₄)alkyl,—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₄alkyl), —O—C(O)—N(C₁₋₄alkyl)₂,—O—(C₁₋₄)alkyl-C(O)H, —O—(C₁₋₄)alkyl-C(O)—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-CO₂H, —O—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-C(O)—NH₂, —O—(C₁₋₄)alkyl-C(O)—NH(C₁₋₄alkyl),—O—(C₁₋₄)alkyl-C(O)—N(C₁₋₄alkyl)₂, —C(O)H, —C(O)—(C₁₋₄)alkyl, —CO₂H,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄alkyl)₂, —SH, —S—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-OH,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH₂,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH(C₁₋₄alkyl),—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂,—S—(C₁₋₄)alkyl-NH(C₁₋₄alkyl), —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH(C₁₋₄alkyl), —SO₂—N(C₁₋₄alkyl)₂, —N—R⁷, cyano, (halo)₁₋₃,hydroxy, nitro, oxo, -cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and-heteroaryl-R⁶.

More preferably, R⁵ is 1 to 2 substituents independently selected fromthe group consisting of hydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶, —N—R⁷,hydroxy and -heteroaryl-R⁶.

Most preferably, R⁵ is 1 to 2 substituents independently selected fromthe group consisting of hydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶, —N—R⁷,hydroxy, -imidazolyl-R⁶, -triazolyl-R⁶ and -tetrazolyl-R⁶.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R⁶ is 1 to 4 substituents attached to a carbon ornitrogen atom independently selected from the group consisting ofhydrogen, —C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C(O)H,—C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂,—C(O)—NH(C₁₋₄alkyl), —C(O)—N(C₁₋₄)alkyl)₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH(C₁₋₄alkyl), —SO₂—N(C₁₋₄alkyl)₂, —(C₁₋₄)alkyl-N—R⁷,—(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-OH, -aryl-R⁸, —(C₁₋₄)alkyl-aryl-R⁸and —(C₁₋₄)alkyl-heteroaryl-R⁸;

-   -   with the proviso that, when R⁶ is attached to a carbon atom, R⁶        is further selected from the group consisting of —C₁₋₄alkoxy,        —(C₁₋₄)alkoxy-(halo)₁₋₃, —SH, —S-(C₁₋₄)alkyl, —N—R⁷, cyano,        halo, hydroxy, nitro, oxo and -heteroaryl-R⁸.

More preferably, R⁶ is hydrogen.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R⁷ is 2 substituents independently selected fromthe group consisting of hydrogen, —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl,—(C₁₋₄)alkyl-NH₂, —(C₁₋₄)alkyl-NH(C₁₋₄alkyl),—(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂, —(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —C(O)H,—C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄alkyl)₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl),—SO₂—N(C₁₋₄alkyl)₂, —C(N)—NH₂, -cycloalkyl-R⁸,—(C₁₋₄)alkyl-heterocyclyl-R⁸, -aryl-R⁸, —(C₁₋₄)alkyl-aryl-R⁸ and—(C₁₋₄)alkyl-heteroaryl-R⁸.

More preferably, R⁷ is 2 substituents independently selected from thegroup consisting of of hydrogen, —C₁₋₄alkyl, —C(O)H, —C(O)—(C₁₋₄)alkyl,—C(O)—O—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl) and—SO₂—N(C₁₋₄alkyl)₂.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R⁸ is 1 to 4 substituents attached to a carbon ornitrogen atom independently selected from the group consisting ofhydrogen, —C₁₋₄alkyl, —(C₁₋₄)alkyl-(halo)₁₋₃ and —(C₁₋₄)alkyl-OH;

-   -   with the proviso that, when R⁸ is attached to a carbon atom, R⁸        is further selected from the group consisting of —C₁₋₄alkoxy,        —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, halo,        —(C₁₋₄)alkoxy-(halo)₁₋₃, hydroxy and nitro.

More preferably, R⁸ is hydrogen.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R⁹ is 1 to 2 substituents independently selectedfrom the group consisting of hydrogen, —C₁₋₄alkoxy, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro.

More preferably, R⁹ is hydrogen.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R² is one substituent attached to a carbon ornitrogen atom selected from the group consisting of hydrogen,—C₁₋₄alkyl-R⁵, —C₂₋₄alkenyl-R⁵, —C₂₋₄alkynyl-R⁵, —C(O)H,—C(O)—(C₁₋₄)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl-R⁹),—C(O)—N(C₁₋₄alkyl-R⁹)₂, —C(O)—NH(aryl-R⁸), —C(O)-cycloalkyl-R⁸,—C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₄)alkyl-R⁹,—SO₂-aryl-R⁸, -cycloalkyl-R⁶, -aryl-R⁶ and —(C₁₋₄)alkyl-N—R⁷;

-   -   with the proviso that, when R² is attached to a carbon atom, R²        is further selected from the group consisting of —C₁₋₄alkoxy-R⁵,        —N—R⁷, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R⁶ and        -heteroaryl-R⁶.

More preferably, R² is one substituent attached to a carbon or nitrogenatom selected from the group consisting of hydrogen, —C₁₋₄alkyl-R⁵,—C₂₋₄alkenyl-R⁵, —C₂₋₄alkynyl-R⁵, —CO₂H, —C(O)—O—(C₁₋₄)alkyl-R⁹,-cycloalkyl-R⁶, -aryl-R⁶ and —(C₁₋₄)alkyl-N—R⁷;

-   -   with the proviso that, when R² is attached to a nitrogen atom, a        quaternium salt is not formed; and, with the proviso that, when        R² is attached to a carbon atom, R² is further selected from the        group consisting of —C₁₋₄alkoxy-R⁵, —N—R⁷, cyano, halogen,        hydroxy, nitro, oxo, -heterocyclyl-R⁶ and -heteroaryl-R⁶.

Most preferably, R² is one substituent attached to a carbon or nitrogenatom selected from the group consisting of hydrogen, —C₁₋₄alkyl-R⁵ and-aryl-R⁶; with the proviso that, when R² is attached to a nitrogen atom,a quaternium salt is not formed; and, with the proviso that when R² isattached to a carbon atom, R² is further selected from the groupconsisting of —N—R⁷, halogen, hydroxy and -heteroaryl-R⁶.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R³ is 1 to 3 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,—C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰,—C(O)H, —C(O)—(C₁₋₄)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl-R⁹),—C(O)—N(C₁₋₄alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸,—C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₈)alkyl-R⁹,—SO₂-aryl-R⁸, —N—R⁷, —(C₁₋₄)alkyl-N—R⁷, cyano, halogen, hydroxy, nitro,-cycloalkyl-R⁸, -heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁵.

More preferably, R³ is one substituent attached to a carbon atomselected from the group consisting of hydrogen, —C₁₋₄alkyl-R¹⁰,—C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰, —C(O)H, —CO₂H,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, halogen, hydroxy and nitro.

Most preferably, R³ is one substituent attached to a carbon atomselected from the group consisting of hydrogen, —C₁₋₄alkyl-R¹⁰, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, halogen and hydroxy.

Embodiments of the present invention include compounds of Formula (I)wherein, R⁴ is 1 to 4 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,—C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰,—C(O)H, —C(O)—(C₁₋₄)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl-R⁹),—C(O)—N(C₁₋₄alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸,—C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SH, —S—(C₁₋₄)alkyl-R¹⁰,—SO₂—(C₁₋₄)alkyl-R⁹, —SO₂-aryl-R⁸, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl-R⁹),—SO₂—N(C₁₋₄alkyl-R⁹)₂, —N—R⁷, cyano, halogen, hydroxy, nitro,-cycloalkyl-R⁸, -heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁸.

Preferably, R⁴ is 1 to 4 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,—C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰,—C(O)H, —CO₂H, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, halogen,hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.

More preferably, R⁴ is 1 to 4 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,C₁₋₄alkyl-R¹⁰, C₁₋₄alkoxy-R¹, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,halogen and hydroxy.

Most preferably, R⁴ is 1 to 4 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,C₁₋₄alkyl-R¹⁰, C₁₋₄alkoxy-R¹⁰, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,chlorine, fluorine and hydroxy.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, R¹⁰ is 1 to 2 substituents independently selectedfrom the group consisting of hydrogen, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, cyano, (halo)₁₋₃, hydroxy, nitro and oxo.

More preferably, R¹⁰ is 1 to 2 substituents independently selected fromthe group consisting of hydrogen and (halo)₁₋₃.

Most preferably, R¹⁰ is 1 to 2 substituents independently selected fromthe group consisting of hydrogen and (fluoro)₃.

Embodiments of the present invention include compounds of Formula (I)wherein, preferably, Y and Z are independently selected from the groupconsisting of O, S, (H,OH) and (H,H); with the proviso that one of Y andZ is O and the other is selected from the group consisting of O, S,(H,OH) and (H,H).

More preferably, Y and Z are independently selected from the groupconsisting of O and (H,H); with the proviso that one of Y and Z is O,and the other is selected from the group consisting of O and (H,H).

Most preferably, Y and Z are independently selected from O.

Exemplified compounds of Formula (I) include compounds selected fromFormula (Ia):

TABLE 1

wherein R, R¹, R², R³ and R⁴ are dependently selected from: Cpd R¹ R³ RR² R⁴ 1 HO(CH₂)₃ H Ph H 2-Cl; 2 Me₂N(CH₂)₃ H Ph H 2-Cl; 3 HO(CH₂)₃ H1-naphthyl H H; 4 Me₂N(CH₂)₃ H 1-naphthyl H H; 5 HO(CH₂)₃ H3-benzo[b]thienyl — 5-Cl; 6 HO(CH₂)₃ H 3-indazolyl H H; 7 HO(CH₂)₃ H7-azaindol-3-yl N-1-ethyl H; 8 HO(CH₂)₃ H Ph H 2-OMe; 9 HO(CH₂)₃ H Ph H3-OMe; 10 HO(CH₂)₃ H Ph H 2-Cl-4-F; 11 HO(CH₂)₃ H Ph H 2-CF₃; 12HO(CH₂)₃ H 2-pyridinyl H H; 13 HO(CH₂)₃ H 2-pyridinyl H 3-Cl-5-CF₃; 14HO(CH₂)₃ H 2-thienyl H H; 15 HO(CH₂)₃ H 3-thienyl H 2,5-Cl₂; 16 HO(CH₂)₃H 1H-pyrazol-3-yl N-1- H; HO(CH₂)₃ 17 HO(CH₂)₃ H 1H-imidazol-2-yl H H;18 HO(CH₂)₃ H 1H-imidazol-4-yl N-1- H; HO(CH₂)₃ 19 HO(CH₂)₃ H1H-imidazol-4-yl N-1- H; HO(CH₂)₂ 20 2-naphthyl H 3-indazolyl N-1- H;Me₂N(CH₂)₃ 21 2-naphthyl H 3-indazolyl N-1- H; HO(CH₂)₃. 22 HO(CH₂)₃ H(CH)₂Ph H 4-F; 23 HO(CH₂)₃ H 3,4-dihydro-2H- H H; pyran-6-yl 24 HO(CH₂)₃H 3-1H-pyrrolyl H H; 25 HO(CH₂)₃ H 2-benzo[b]furyl H H; 26 HO(CH₂)₃ H1H-pyrazol-3-yl N-1-CH₃ H; 27 HO(CH₂)₃ H CN — — 28 HO(CH₂)₃ Hdibenzo[b,d]thien-4-yl H H; 29 HO(CH₂)₃ H 4-dibenzofuryl H H; 30MeO(CH₂)₃ H Ph H 2-OH; 31 MeO(CH₂)₃ H Ph H 3,4-(OMe)₂; 32 HO(CH₂)₃ H PhH 3,4-(OH)₂; 33 2-naphthyl H Ph H 2-OMe; 34 Boc-NH(CH₂)₃ H Ph H 2-OMe;35 MeOC(O)— H Ph H 2-OMe NH(CH₂)₃ 36 Boc-NH(CH₂)₃ H Ph H 2-CF₃; 37MeOC(O)— H Ph H 2-CF₃ NH(CH₂)₃ 38 H₂N(CH₂)₃ H Ph H 2-OMe; 39 H₂N—SO₂— HPh H 2-OMe NH(CH₂)₃ 40 HO(CH₂)₃ H Pyrimidin-5-yI 2-OMe 4-OMe 41 HO(CH₂)₃H Pyrimidin-5-yI H H 42 HO(CH₂)₃ H Quinolin-8-yI H H 43 HO(CH₂)₃ HBenzo[b]thiophen H H 44 HO(CH₂)₃ H isoxazol-4-yl 3-Me 5-Me 45 HO(CH₂)₃ H2-oxo-2H-pyran-3-yl H H 46 HO(CH₂)₃ H 1H-Pyrroly-3-yl 1-Me H 47 HO(CH₂)₃H pyrazin-2-yl H H 48 HO(CH₂)₃ H 1H-Pyrroly-3-yl 1-benzyl H 49 HO(CH₂)₃H oxazol-5-yl 2-phenyl H 50 HO(CH₂)₃ H 5,6-Dihydro-4H- H Hpyrrolo[1,2-b]pyrazol- 2-yl 51 HO(CH₂)₃ H 5,6-Dihydro- H H[1,4]dioxin-2-yl 52 HO(CH₂)₃ H 1H-pyrazol-4-yl 1-Me H 53 HO(CH₂)₃ HFuran-2-yl H H 54 HO(CH₂)₃ H 4,5,6,7-tetrahydro- H H pyrazolo[1,5-a]pyridin-2-yl 55 HO(CH₂)₃ H thiazol- H H 2-yl 56 HO(CH₂)₃ Hpyrimidin-2-yl H H 57 Ph(CH₂)₃ H pyrimidin-5-yl 2-MeO 4-MeO 58 Ph(CH₂)₃H pyrimidin-5-yl H H 59 Ph(CH₂)₃ H 5,6-Dihydro-4H- H Hpyrrolo[1,2-b]pyrazol- 2-yl 60 Ph(CH₂)₃ H pyrazin-2-yl H H 61 Ph(CH₂)₃ H5,6-Dihydro-4H- H H pyran-2-yl 62 NC(CH₂)₃ H pyrimidin-5-yl 2-Meo 4-MeO63 NC(CH₂)₃ H pyrazin-2-yl H H 64 NC(CH₂)₃ H 1H-pyrazol-3-yl 1-Me H 65PhO(CH₂)₃ H 5,6-Dihydro-4H- H H pyrrolo[1,2-b]pyrazol- 2-yl 66 HO(CH₂)₃H 2H-pyrazol-3-yl 2-Me H 67 HO(CH₂)₃ H 3-Furan-3-yl H H 68 HO(CH₂)₃ H1H-pyrimidine-2,4- H H dione-5-yl 69 NC(CH₂)₂ H 1H-pyrazol-3-yl 1-Me H70 HO(CH₂)₃ H CH₃(CH₂)₃ — — 71 MeO(CH₂)₂ H pyrimidin-5-yl 2-MeO 4-MeO 72PhCH₂ H pyrimidin-5-yl 2-MeO 4-MeO 73 Ph(CH₂)₂ H pyrimidin-5-yl 2-MeO4-MeO 74 3-thiophen-2-yl- H pyrimidin-5-yl 2-MeO 4-MeO propyl 752-(4-fluoro- H pyrimidin-5-yl 2-MeO 4-MeO phenoxy)-ethyl 76 PhO(CH₂)₃ Hpyrimidin-5-yl 2-MeO 4-MeO 77 MeC(O)— H Ph H 2-OMe NH(CH₂)₃ 78HC(O)—NH(CH₂)₃ H Ph H 2-OMe 79 MeSO₂—NH(CH₂)₃ H Ph H 2-OMe

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201–217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts may, however, beuseful in the preparation of compounds according to this invention or oftheir pharmaceutically acceptable salts. Representative organic orinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The term “independently” means that when a group is substituted withmore than one substituent that the substituents may be the same ordifferent. The term “dependently” means that the substituents arespecified in an indicated combination of structure variables.

Unless specified otherwise, the term “alkyl” refers to a saturatedstraight or branched chain consisting solely of 1–8 hydrogen substitutedcarbon atoms; preferably, 1–6 hydrogen substituted carbon atoms; and,most preferably, 1–4 hydrogen substituted carbon atoms. The term“alkenyl” refers to a partially unsaturated straight or branched chainconsisting solely of 2–8 hydrogen substituted carbon atoms that containsat least one double bond. The term “alkynyl” refers to a partiallyunsaturated straight or branched chain consisting solely of 2–8 hydrogensubstituted carbon atoms that contains at least one triple bond. Theterm “alkoxy” refers to —O-alkyl, where alkyl is as defined supra. Theterm “hydroxyalkyl” refers to radicals wherein the alkyl chainterminates with a hydroxy radical of the formula HO-alkyl, where alkylis as defined supra. Alkyl, alkenyl and alkynyl chains are optionallysubstituted within the alkyl chain or on a terminal carbon atom.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic alkyl ring consisting of 3–8 hydrogen substituted carbonatoms or a saturated or partially unsaturated bicyclic ring consistingof 8 or 11 hydrogen substituted carbon atoms. Examples include, and arenot limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “heterocyclyl” as used herein refers to an unsubstituted orsubstituted stable three to seven membered monocyclic saturated orpartially unsaturated ring system which consists of carbon atoms andfrom one to three heteroatoms selected from N, O or S, or a stable eightto twelve membered bicyclic saturated or partially saturated ring systemwhich consists of carbon atoms and from one to four heteroatoms selectedfrom N, O, or S. In either the monocyclic or bicyclic rings the nitrogenor sulfur heteroatoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. Preferred are saturated orpartially unsaturated rings having five or six members of which at leastone member is a N, O or S atom and which optionally contains oneadditional N, O or S atoms; saturated or partially unsaturated bicyclicrings having nine or ten members of which at least one member is a N, Oor S atom and which optionally contains one or two additional N, O or Satoms; wherein said nine or ten membered bicyclic rings may have onearomatic ring and one nonaromatic ring. In another embodiment of thisinvention the previously defined heterocyclyl have as the additionalheteroatom N, wherein at most two nitrogens atoms are adjacent. Examplesinclude, and are not limited to, pyrrolinyl, pyrrolidinyl,1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl,5,6-dihydro-4H-pyrrolo[1,2-b]prazolyl and4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl.

The term “aryl” refers to an aromatic monocyclic ring containing 6hydrogen substituted carbon atoms, an aromatic bicyclic ring systemcontaining 10 hydrogen substituted carbon atoms or an aromatic tricyclicring system containing 14 hydrogen substituted carbon atoms. Examplesinclude, and are not limited to, phenyl, naphthalenyl or anthracenyl.

The term “heteroaryl” as used herein represents an unsubstituted orsubstituted stable five or six membered monocyclic aromatic ring systemor an unsubstituted or substituted stable nine or ten memberedbenzo-fused heteroaromatic ring system (wherein both rings of thebenzo-fused system are aromatic) or bicyclic heteroaromatic ring systemand unsubstituted or substituted stable twelve to fourteen memberedtricyclic ring systems which consists of carbon atoms and from one tofour heteroatoms selected from N, O or S, and wherein the nitrogen orsulfur heteroatoms of any of these heteroaryls may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized.Preferred heteroaryl are aromatic monocyclic rings containing fivemembers of which at least one member is a N, O or S atom and whichoptionally contains one, two or three additional N atoms; an aromaticmonocyclic ring having six members of which one, two or three membersare a N atoms; an aromatic bicyclic ring having nine members of which atleast one member is a N, O or S atom and which optionally contains one,two or three additional N atoms; an aromatic bicyclic ring having tenmembers of which of which one, two, three or four members are N atoms;or, an aromatic tricyclic ring system containing 13 members of which atleast one member is a N, O or S atom and which optionally contains one,two or three additional N atoms. In another embodiment of thisinvention, the previously defined heteroaryls have as the additionalheteroatom N, wherein at most two nitrogens atoms are adjacent. Examplesinclude, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,indazolyl, benzo(b)thienyl, benzofuryl, quinolinyl, isoquinolinyl,quinazolinyl, dibenzofuryl or dibenzo[b,d]thienyl.

The “carboxyl” as used herein refers to the organic radical terminalgroup: R—C(O)OH.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., aralkyl, alkylamino) it shallbe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁–C₆) shall referindependently to the number of carbon atoms in an alkyl or cycloalkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

Unless indicated otherwise, under standard nomenclature rules usedthroughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenyl(C₁₋₆)alkylamido(C₁₋₆)alkyl” substituent refers to a group of theformula:

When the substituent's point of attachment is not otherwise clear, adashed line is used to indicate the point of attachment, followed by theadjacent functionality and ending with the terminal functionality suchas, for example, —(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

An embodiment of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. Illustrative of the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. Another illustration ofthe invention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier. Further illustrative of the presentinvention are pharmaceutical compositions comprising one or morecompounds of this invention in association with a pharmaceuticallyacceptable carrier.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The compounds of the present invention are selective kinase inhibitorsand some compounds are dual-kinase inhibitors useful in a method fortreating or ameliorating a kinase or dual-kinase mediated disorder. Inparticular, the kinase is selected from protein kinase C or glycogensynthase kinase-3. More particularly, the kinase is selected fromprotein kinase C α, protein kinase C β (e.g. protein kinase C β-I andprotein kinase C β-II), protein kinase C γ or glycogen synthasekinase-3β.

Protein Kinase C Isoforms

Protein kinase C is known to play a key role in intracellular signaltransduction (cell-cell signaling), gene expression and in the controlof cell differentiation and growth. The PKC family is composed of twelveisoforms that are further classified into 3 subfamilies: the calciumdependent classical PKC isoforms alpha (α), beta-I (β-I), beta-II (β-II)and gamma (γ); the calcium independent PKC isoforms delta (γ), epsilon(δ), eta (η), theta (θ) and mu (μ); and, the a typical PKC isoforms zeta(ζ), lambda (λ) and iota (ι).

Certain disease states tend to be associated with elevation ofparticular PKC isoforms. The PKC isoforms exhibit distinct tissuedistribution, subcellular localization and activation-dependentcofactors. For example, the α and β isoforms of PKC are selectivelyinduced in vascular cells stimulated with agonists such as vascularendothelial growth factor (VEGF) (P. Xia, et al., J. Clin. Invest.,1996, 98, 2018) and have been implicated in cellular growth,differentiation, and vascular permeability (H. Ishii, et al., J. Mol.Med., 1998, 76, 21). The elevated blood glucose levels found in diabetesleads to an isoform-specific elevation of the β-II isoform in vasculartissues (Inoguchi, et al., Proc. Natl. Acad. Sci. USA, 1992, 89,11059–11065). A diabetes-linked elevation of the β isoform in humanplatelets has been correlated with their altered response to agonists(Bastyr III, E. J. and Lu, J., Diabetes, 1993, 42, (Suppl. 1) 97A). Thehuman vitamin D receptor has been shown to be selectively phosphorylatedby PKCβ. This phosphorylation has been linked to alterations in thefunctioning of the receptor (Hsieh, et al., Proc. Natl. Acad. Sci. USA,1991, 88, 9315–9319; Hsieh, et al., J. Biol. Chem., 1993, 268,15118–15126). In addition, the work has shown that the β-II isoform isresponsible for erythroleukemia cell proliferation while the ox isoformis involved in megakaryocyte differentiation in these same cells(Murray, et al., J. Biol. Chem., 1993, 268, 15847–15853).

Cardiovascular Diseases

PKC activity plays an important role in cardiovascular diseases.Increased PKC activity in the vasculature has been shown to causeincreased vasoconstriction and hypertension (Bilder, G. E., et al., J.Pharmacol. Exp. Ther., 1990, 252, 526–530). PKC inhibitors blockagonist-induced smooth muscle cell proliferation (Matsumoto, H. andSasaki, Y., Biochem. Biophys. Res. Commun., 1989, 158, 105–109). PKC βtriggers events leading to induction of Egr-1 (Early Growth Factor-1)and tissue factor under hypoxic conditions (as part of the oxygendeprivation-mediated pathway for triggering procoagulant events) (Yan,S-F, et al., J. Biol. Chem., 2000, 275, 16, 11921–11928). PKC β issuggested as a mediator for production of PAI-1 (Plaminogen ActivatorInhibitor-1) and is implicated in the development of thrombosis andatherosclerosis (Ren, S, et al., Am. J. Physiol., 2000, 278, (4, Pt. 1),E656–E662). PKC inhibitors are useful in treating cardiovascularischemia and improving cardiac function following ischemia (Muid, R. E.,et al., FEBS Lett., 1990, 293, 169–172; Sonoki, H. et al., Kokyu-ToJunkan, 1989, 37, 669–674). Elevated PKC levels have been correlatedwith an increased platelet function response to agonists (Bastyr III, E.J. and Lu, J., Diabetes, 1993, 42, (Suppl. 1) 97A). PKC has beenimplicated in the biochemical pathway in the platelet-activating factor(PAF) modulation of microvascular permeability (Kobayashi, et al., Amer.Phys. Soc., 1994, H1214–H1220). PKC inhibitors affect agonist-inducedaggregation in platelets (Toullec, D., et al., J. Biol. Chem., 1991,266, 15771–15781). Accordingly, PKC inhibitors may be indicated for usein treating cardiovascular disease, ischemia, thrombotic conditions,atherosclerosis and restenosis.

Diabetes

Excessive activity of PKC has been linked to insulin signaling defectsand therefore to the insulin resistance seen in Type II diabetes(Karasik, A., et al., J. Biol. Chem., 1990, 265, 10226–10231; Chen, K.S., et al., Trans. Assoc. Am. Physicians, 1991, 104, 206–212; Chin, J.E., et al., J. Biol. Chem., 1993, 268, 6338–6347).

Diabetes-Associated Disorders

Studies have demonstrated an increase in PKC activity in tissues knownto be susceptible to diabetic complications when exposed tohyperglycemic conditions (Lee, T-S., et al., J. Clin. Invest., 1989, 83,90–94; Lee, T-S., et al., Proc. Natl. Acad. Sci. USA, 1989, 86,5141–5145; Craven, P. A. and DeRubertis, F. R., J. Clin. Invest., 1989,87, 1667–1675; Wolf, B. A., et al., J. Clin. Invest., 1991, 87, 31–38;Tesfamariam, B., et al., J. Clin. Invest., 1991, 87, 1643–1648). Forexample, activation of the PKC-β-II isoform plays an important role indiabetic vascular complications such as retinopathy (Ishii, H., et al.,Science, 1996, 272, 728–731) and PKCβ has been implicated in developmentof the cardiac hypertrophy associated with heart failure (X. Gu, et al.,Circ. Res., 1994, 75, 926; R. H. Strasser, et al., Circulation, 1996,94, 1551). Overexpression of cardiac PKCβII in transgenic mice causedcardiomyopathy involving hypertrophy, fibrosis and decreased leftventricular function (H. Wakasaki, et al., Proc. Natl. Acad. Sci. USA,1997, 94, 9320).

Inflammatory Diseases

PKC inhibitors block inflammatory responses such as the neutrophiloxidative burst, CD3 down-regulation in T-lymphocytes andphorbol-induced paw edema (Twoemy, B., et al., Biochem. Biophys. Res.Commun., 1990, 171, 1087–1092; Mulqueen, M. J., et al. Agents Actions,1992, 37, 85–89). PKC β has an essential role in the degranulation ofbone marrow-derived mast cells, thus affecting cell capacity to produceIL-6 (Interleukin-6) (Nechushtan, H., et al., Blood, 2000 (March), 95,5, 1752–1757). PKC plays a role in enhanced ASM (Airway Smooth Muscle)cell growth in rat models of two potential risks for asthma:hyperresponsiveness to contractile agonists and to growth stimuli (Ren,S, et al., Am. J. Physiol., 2000, 278, (4, Pt. 1), E656–E662). PKC β-1overexpression augments an increase in endothelial permeability,suggesting an important function in the regulation of the endothelialbarrier (Nagpala, P. G., et al., J. Cell Physiol., 1996, 2, 249–55). PKCβ mediates activation of neutrophil NADPH oxidase by PMA and bystimulation of Fcγ receptors in neutrophils (Dekker, L. V., et al.,Biochem. J., 2000, 347, 285–289). Thus, PKC inhibitors may be indicatedfor use in treating inflammation and asthma.

Immunological Disorders

PKC may be useful in treating or ameliorating certain immunologicaldisorders. While one study suggests that HCMV (Human Cytomegalovirus)inhibition is not correlated with PKC inhibition (Slater, M. J., et al.,Biorg. & Med. Chem., 1999, 7, 1067–1074), another study showed that thePKC signal transduction pathway synergistically interacted with thecAMP-dependent PKA pathway to activate or increase HIV-1 transcriptionand viral replication and was abrogated with a PKC inhibitor (Rabbi, M.F., et al., Virology, 1998 (June 5), 245, 2, 257–69). Therefore, animmunological disorder may be treated or ameliorated as a function ofthe affected underlying pathway's response to up- or down-regulation ofPKC.

PKC β deficiency also results in an immunodeficiency characterized byimpaired humoral immune responses and a reduced B cell response, similarto X-linked immunodeficiency in mice, playing an important role inantigen receptor-mediated signal transduction (Leitges, M., et al.,Science (Wash., D.C.), 1996, 273, 5276, 788–789). Accordingly,transplant tissue rejection may be ameliorated or prevented bysuppressing the immune response using a PKC β inhibitor.

Dermatological Disorders

Abnormal activity of PKC has been linked to dermatological disorderscharacterized by abnormal proliferation of keratinocytes, such aspsoriasis (Horn, F., et al., J. Invest. Dermatol., 1987, 88, 220–222;Raynaud, F. and Evain-Brion, D., Br. J. Dermatol., 1991, 124, 542–546).PKC inhibitors have been shown to inhibit keratinocyte proliferation ina dose-dependent manner (Hegemann, L., et al., Arch. Dermatol. Res.,1991, 283, 456–460; Bollag, W. B., et al., J. Invest. Dermatol., 1993,100, 240–246).

Oncological Disorders

PKC activity has been associated with cell growth, tumor promotion andcancer (Rotenberg, S. A. and Weinstein, I. B., Biochem. Mol. AspectsSel. Cancer, 1991, 1, 25–73; Ahmad, et al., Molecular Pharmacology,1993, 43, 858–862); PKC inhibitors are known to be effective inpreventing tumor growth in animals (Meyer, T., et al., Int. J. Cancer,1989, 43, 851–856; Akinagaka, S., et al., Cancer Res., 1991, 51,4888–4892). PKC β-1 and β-2 expression in differentiated HD3 coloncarcinoma cells blocked their differentiation, enabling them toproliferate in response to basic FGF (Fibroblast Growth Factor) likeundifferentiated cells, increasing their growth rate and activatingseveral MBP (Myelin-Basic Protein) kinases, including p57 MAP(Mitogen-Activated Protein) kinase (Sauma, S., et al., Cell GrowthDiffer., 1996, 7, 5, 587–94). PKC α inhibitors, having an additivetherapeutic effect in combination with other anti-cancer agents,inhibited the growth of lymphocytic leukemia cells (Konig, A., et al.,Blood, 1997, 90, 10, Suppl. 1 Pt. 2). PKC inhibitors enhanced MMC(Mitomycin-C) induced apoptosis in a time-dependent fashion in a gastriccancer cell-line, potentially indicating use as agents forchemotherapy-induced apoptosis (Danso, D., et al., Proc. Am. Assoc.Cancer Res., 1997, 38, 88 Meet., 92). Therefore, PKC inhibitors may beindicated for use in ameliorating cell and tumor growth, in treating orameliorating cancers (such as leukemia or colon cancer) and as adjunctsto chemotherapy.

PKC α (by enhancing cell migration) may mediate some proangiogeniceffects of PKC activation while PKC δ may direct antiangiogenic effectsof overall PKC activation (by inhibiting cell growth and proliferation)in capillary endothelial cells, thus regulating endothelialproliferation and angiogenesis (Harrington, E. O., et al., J. Biol.Chem., 1997, 272, 11, 7390–7397). PKC inhibitors inhibit cell growth andinduce apoptosis in human glioblastoma cell lines, inhibit the growth ofhuman astrocytoma xenografts and act as radiation sensitizers inglioblastoma cell lines (Begemann, M., et al., Anticancer Res. (Greece),1998 (Jul–Aug), 18, 4A, 2275–82). PKC inhibitors, in combination withother anti-cancer agents, are radiation and chemosensitizers useful incancer therapy (Teicher, B. A., et al., Proc. Am. Assoc. Cancer Res.,1998, 39, 89 Meet., 384). PKC β inhibitors (by blocking the MAP kinasesignal transduction pathways for VEGF (Vascular Endothelial GrowthFactor) and bFGF (basic Fibrinogen Growth Factor) in endothelial cells),in a combination regimen with other anti-cancer agents, have ananti-angiogenic and antitumor effect in a human T98G glioblastomamultiforme xenograft model (Teicher, B. A., et al., Clinical CancerResearch, 2001 (March), 7, 634–640). Accordingly, PKC inhibitors may beindicated for use in ameliorating angiogenesis and in treating orameliorating cancers (such as breast, brain, kidney, bladder, ovarian orcolon cancers) and as adjuncts to chemotherapy and radiation therapy.

Central Nervous System Disorders

PKC activity plays a central role in the functioning of the centralnervous system (CNS) (Huang, K. P., Trends Neurosci., 1989, 12, 425–432)and PKC is implicated in Alzheimer's disease (Shimohama, S., et al.,Neurology, 1993, 43, 1407–1413) and inhibitors have been shown toprevent the damage seen in focal and central ischemic brain injury andbrain edema (Hara, H., et al., J. Cereb. Blood Flow Metab., 1990, 10,646–653; Shibata, S., et al., Brain Res., 1992, 594, 290–294).Accordingly, PKC inhibitors may be indicated for use in treatingAlzheimer's disease and in treating neurotraumatic and ischemia-relateddiseases.

The long-term increase in PKC γ (as a component of the phosphoinositide2^(nd) messenger system) and muscarinic acetylcholine receptorexpression in an amygdala-kindled rat model has been associated withepilepsy, serving as a basis for the rat's permanent state ofhyperexcitability (Beldhuis, H. J. A., et al., Neuroscience, 1993, 55,4, 965–73). Therefore, PKC inhibitors may be indicated for use intreating epilepsy.

The subcellular changes in content of the PKC γ and PKC β-II isoenzymesfor animals in an in-vivo thermal hyperalgesia model suggests thatperipheral nerve injury contributes to the development of persistentpain (Miletic, V., et al., Neurosci. Lett., 2000, 288, 3, 199–202). Micelacking PKC γ display normal responses to acute pain stimuli, but almostcompletely fail to develop a neuropathic pain syndrome after partialsciatic nerve section (Chen, C., et al., Science (Wash., D.C.), 1997,278, 5336, 279–283). PKC modulation may thus be indicated for use intreating chronic pain and neuropathic pain.

PKC has demonstrated a role in the pathology of conditions such as, butnot limited to, cardiovascular diseases, diabetes, diabetes-associateddisorders, inflammatory diseases, immunological disorders,dermatological disorders, oncological disorders and central nervoussystem disorders. Glycogen Synthase Kinase-3 Glycogen synthase kinase-3(GSK-3) is a serine/threonine protein kinase composed of two isoforms (αand β) which are encoded by distinct genes. GSK-3 is one of severalprotein kinases which phosphorylate glycogen synthase (GS) (Embi, etal., Eur. J. Biochem, 1980, 107, 519–527). The α and β isoforms have amonomeric structure of 49 and 47 kD respectively and are both found inmammalian cells. Both isoforms phosphorylate muscle glycogen synthase(Cross, et al., Biochemical Journal, 1994, 303, 21–26) and these twoisoforms show good homology between species (human and rabbit GSK-3α are96% identical).

Diabetes

Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus, NIDDM) isa multifactorial disease. Hyperglycemia is due to insulin resistance inthe liver, muscle and other tissues coupled with inadequate or defectivesecretion of insulin from pancreatic islets. Skeletal muscle is themajor site for insulin-stimulated glucose uptake and in this tissueglucose removed from the circulation is either metabolised throughglycolysis and the TCA (tricarboxylic acid) cycle or stored as glycogen.Muscle glycogen deposition plays the more important role in glucosehomeostasis and Type II diabetic subjects have defective muscle glycogenstorage. The stimulation of glycogen synthesis by insulin in skeletalmuscle results from the dephosphorylation and activation of glycogensynthase (Villar-Palasi C. and Larner J., Biochim. Biophys. Acta, 1960,39, 171–173, Parker P. J., et al., Eur. J. Biochem., 1983, 130, 227–234,and Cohen P., Biochem. Soc. Trans., 1993, 21, 555–567). Thephosphorylation and dephosphorylation of GS are mediated by specifickinases and phosphatases. GSK-3 is responsible for phosphorylation anddeactivation of GS, while glycogen bound protein phosphatase 1 (PP1G)dephosphorylates and activates GS. Insulin both inactivates GSK-3 andactivates PP1G (Srivastava A. K. and Pandey S. K., Mol. and CellularBiochem., 1998, 182, 135–141).

Studies suggest that an increase in GSK-3 activity might be important inType II diabetic muscle (Chen, et al., Diabetes, 1994, 43, 1234–1241).Overexpression of GSK-3β and constitutively active GSK-3β (S9A, S9e)mutants in HEK-293 cells resulted in suppression of glycogen synthaseactivity (Eldar-Finkelman, et al., PNAS, 1996, 93, 10228–10233) andoverexpression of GSK-3β in CHO cells, expressing both insulin receptorand insulin receptor substrate 1 (IRS-1) resulted in impairment ofinsulin action (Eldar-Finkelman and Krebs, PNAS, 1997, 94, 9660–9664).Recent evidence for the involvement of elevated GSK-3 activity and thedevelopment of insulin resistance and Type II diabetes in adipose tissuehas emerged from studies undertaken in diabetes and obesity proneC57BL/6J mice (Eldar-Finkelman, et al., Diabetes, 1999, 48, 1662–1666).

Dermatological Disorders

The finding that transient β-catenin stabilization may play a role inhair development (Gat, et al., Cell, 1998, 95, 605–614) suggests thatGSK-3 inhibitors could also be used in the treatment of baldness.

Inflammatory Diseases

Studies on fibroblasts from the GSK-3β knockout mouse indicate thatinhibition of GSK-3 may be useful in treating inflammatory disorders ordiseases through the negative regulation of NFkB activity (Hoeflich K.P., et al., Nature, 2000, 406, 86–90).

Central Nervous System Disorders

In addition to modulation of glycogen synthase activity, GSK-3 alsoplays an important role in the CNS disorders. GSK-3 inhibitors may be ofvalue as neuroprotectants in the treatment of acute stroke and otherneurotraumatic injuries (Pap and Cooper, J. Biol. Chem., 1998, 273,19929–19932). Lithium, a low mM inhibitor of GSK-3, has been shown toprotect cerebellar granule neurons from death (D'Mello, et al., Exp.Cell Res., 1994, 211, 332–338) and chronic lithium treatment hasdemonstrable efficacy in the middle cerebral artery occlusion model ofstroke in rodents (Nonaka and Chuang, Neuroreport, 1998, 9(9),2081–2084).

Tau and β-catenin, two known in vivo substrates of GSK-3, are of directrelevance in consideration of further aspects of the value of GSK-3inhibitors in relation to treatment of chronic neurodegenerativeconditions. Tau hyperphosphorylation is an early event inneurodegenerative conditions such as Alzheimer's disease and ispostulated to promote microtubule disassembly. Lithium has been reportedto reduce the phosphorylation of tau, enhance the binding of tau tomicrotubules and promote microtubule assembly through direct andreversible inhibition of GSK-3 (Hong M. et al J. Biol. Chem., 1997, 272(40), 25326–32). β-catenin is phosphorylated by GSK-3 as part of atripartite axin protein complex resulting in β-catenin degradation(Ikeda, et al., EMBO J., 1998, 17, 1371–1384). Inhibition of GSK-3activity is involved in the stabilization of catenin hence promotesβ-catenin-LEF-1/TCF transcriptional activity (Eastman, Grosschedl, Curr.Opin. Cell Biol., 1999, 11, 233). Studies have also suggested that GSK-3inhibitors may also be of value in treatment of schizophrenia (CotterD., et al. Neuroreport, 1998, 9, 1379–1383; Lijam N., et al., Cell,1997, 90, 895–905) and manic depression (Manji, et al., J. Clin.Psychiatry, 1999, 60, (Suppl 2) 27–39 for review).

Accordingly, compounds found useful as GSK-3 inhibitors could havefurther therapeutic utility in the treatment of diabetes, dermatologicaldisorders, inflammatory diseases and central nervous system disorders.

Embodiments of the method of the present invention include a method fortreating or ameliorating a kinase or dual-kinase mediated disorder in asubject in need thereof comprising administering to the subject atherapeutically effective amount of an instant compound orpharmaceutical composition thereof. The therapeutically effective amountof the compounds of Formula (I) exemplified in such a method is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.

Embodiments of the present invention include the use of a compound ofFormula (I) for the preparation of a medicament for treating orameliorating a kinase or dual-kinase mediated disorder in a subject inneed thereof.

In accordance with the methods of the present invention, an individualcompound of the present invention or a pharmaceutical compositionthereof can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms. The instant invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term“administering” is to be interpreted accordingly.

Embodiments of the present method include a compound or pharmaceuticalcomposition thereof advantageously co-administered in combination withother agents for treating or ameliorating a kinase or dual-kinasemediated disorder. For example, in the treatment of diabetes, especiallyType II diabetes, a compound of Formula (I) or pharmaceuticalcomposition thereof may be used in combination with other agents,especially insulin or antidiabetic agents including, but not limited to,insulin secretagogues (such as sulphonylureas), insulin sensitizersincluding, but not limited to, glitazone insulin sensitizers (such asthiazolidinediones) or biguamides or a glucosidase inhibitors.

The combination product comprises co-administration of a compound ofFormula (I) or pharmaceutical composition thereof and an additionalagent for treating or ameliorating a kinase or dual-kinase mediateddisorder, the sequential administration of a compound of Formula (I) orpharmaceutical composition thereof and an additional agent for treatingor ameliorating a kinase or dual-kinase mediated disorder,administration of a pharmaceutical composition containing a compound ofFormula (I) or pharmaceutical composition thereof and an additionalagent for treating or ameliorating a kinase or dual-kinase mediateddisorder or the essentially simultaneous administration of a separatepharmaceutical composition containing a compound of Formula (I) orpharmaceutical composition thereof and a separate pharmaceuticalcomposition containing an additional agent for treating or amelioratinga kinase or dual-kinase mediated disorder.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or human,that is being sought by a researcher, veterinarian, medical doctor, orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

The ubiquitous nature of the PKC and GSK isoforms and their importantroles in physiology provide incentive to produce highly selective PKCand GSK inhibitors. Given the evidence demonstrating linkage of certainisoforms to disease states, it is reasonable to assume that inhibitorycompounds that are selective to one or two PKC isoforms or to a GSKisoform relative to the other PKC and GSK isoforms and other proteinkinases are superior therapeutic agents. Such compounds shoulddemonstrate greater efficacy and lower toxicity by virtue of theirspecificity. Accordingly, it will be appreciated by one skilled in theart that a compound of Formula (I) is therapeutically effective forcertain kinase or dual-kinase mediated disorders based on the modulationof the disorder by selective kinase or dual-kinase inhibition. Theusefulness of a compound of Formula (I) as a selective kinase ordual-kinase inhibitor can be determined according to the methodsdisclosed herein and the scope of such use includes use in one or morekinase or dual-kinase mediated disorders.

Therefore, the term “kinase or dual-kinase mediated disorders” as usedherein, includes, and is not limited to, cardiovascular diseases,diabetes, diabetes-associated disorders, inflammatory diseases,immunological disorders, dermatological disorders, oncological disordersand CNS disorders.

Cardiovascular diseases include, and are not limited to, acute stroke,heart failure, cardiovascular ischemia, thrombosis, atherosclerosis,hypertension, restenosis, retinopathy of prematurity or age-relatedmacular degeneration. Diabetes includes insulin dependent diabetes orType II non-insulin dependent diabetes mellitus. Diabetes-associateddisorders include, and are not limited to, impaired glucose tolerance,diabetic retinopathy, proliferative retinopathy, retinal vein occlusion,macular edema, cardiomyopathy, nephropathy or neuropathy. Inflammatorydiseases include, and are not limited to, vascular permeability,inflammation, asthma, rheumatoid arthritis or osteoarthritis.Immunological disorders include, and are not limited to, transplanttissue rejection, HIV-1 or immunological disorders treated orameliorated by PKC modulation. Dermatological disorders include, and arenot limited to, psoriasis, hair loss or baldness. Oncological disordersinclude, and are not limited to, cancers or tumor growth (such asbreast, brain, kidney, bladder, ovarian or colon cancer or leukemia),proliferative angiopathy and angiogenesis; and, includes use forcompounds of Formula (I) as an adjunct to chemotherapy and radiationtherapy. CNS disorders include, and are not limited to, chronic pain,neuropathic pain, epilepsy, chronic neurodegenerative conditions (suchas dementia or Alzheimer's disease), mood disorders (such asschizophrenia), manic depression or neurotraumatic, cognitive declineand ischemia-related diseases {as a result of head trauma (from acuteischemic stroke, injury or surgery) or transient ischemic stroke (fromcoronary bypass surgery or other transient ischemic conditions)}.

A compound may be administered to a subject in need of treatment by anyconventional route of administration including, but not limited to oral,nasal, sublingual, ocular, transdermal, rectal, vaginal and parenteral(i.e. subcutaneous, intramuscular, intradermal, intravenous etc.).

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1–3, edited by Lieberman,et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes1–2, edited by Avis, et al.; and Pharmaceutical Dosage Forms: DisperseSystems, Volumes 1–2, edited by Lieberman, et al.; published by MarcelDekker, Inc.

In preparing a pharmaceutical composition of the present invention inliquid dosage form for oral, topical and parenteral administration, anyof the usual pharmaceutical media or excipients may be employed. Thus,for liquid dosage forms, such as suspensions (i.e. colloids, emulsionsand dispersions) and solutions, suitable carriers and additives includebut are not limited to pharmaceutically acceptable wetting agents,dispersants, flocculation agents, thickeners, pH control agents (i.e.buffers), osmotic agents, coloring agents, flavors, fragrances,preservatives (i.e. to control microbial growth, etc.) and a liquidvehicle may be employed. Not all of the components listed above will berequired for each liquid dosage form.

In solid oral preparations such as, for example, powders, granules,capsules, caplets, gelcaps, pills and tablets (each including immediaterelease, timed release and sustained release formulations), suitablecarriers and additives include but are not limited to diluents,granulating agents, lubricants, binders, glidants, disintegrating agentsand the like. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form, in whichcase solid pharmaceutical carriers are obviously employed. If desired,tablets may be sugar coated, gelatin coated, film coated or entericcoated by standard techniques.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful and the like, anamount of the active ingredient necessary to deliver an effective doseas described above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about300 mg (preferably, from about 0.1 mg to about 100 mg; and, morepreferably, from about 0.1 mg to about 30 mg) and may be given at adosage of from about 0.01 mg/kg/day to about 300 mg/kg/day (preferably,from about 0.1 mg/kg/day to about 100 mg/kg/day; and, more preferably,from about 0.1 mg/kg/day to about 30 mg/kg/day). Preferably, in themethod for the treatment of kinase mediated disorders described in thepresent invention and using any of the compounds as defined herein, thedosage form will contain a pharmaceutically acceptable carriercontaining between about 0.01 mg and 100 mg; and, more preferably,between about 5 mg and 50 mg of the compound; and, may be constitutedinto any form suitable for the mode of administration selected. Thedosages, however, may be varied depending upon the requirement of thesubjects, the severity of the condition being treated and the compoundbeing employed. The use of either daily administration or post-periodicdosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, lozenges, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories for administration byoral, intranasal, sublingual, intraocular, transdermal, parenteral,rectal, vaginal, inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and glidants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable glidants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W. R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate), polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, methacrylate and ethylacrylate copolymers, methacrylate andmethyl methacrylate copolymers and the like. Sustained release tabletsmay also be made by film coating or wet granulation using slightlysoluble or insoluble substances in solution (which for a wet granulationacts as the binding agents) or low melting solids a molten form (whichin a wet granulation may incorporate the active ingredient). Thesematerials include natural and synthetic polymers waxes, hydrogenatedoils, fatty acids and alcohols (i.e. beeswax, carnauba wax, cetylalcohol, cetylstearyl alcohol, and the like), esters of fatty acidsmetallic soaps, and other acceptable materials that can be used togranulate, coat, entrap or otherwise limit the solubility of an activeingredient to achieve a prolonged or sustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include, but are not limited to polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, tohomopolymers and copolymers (which means polymers containing two or morechemically distinguishable repeating units) of lactide (which includeslactic acid d-, I- and meso lactide), glycolide (including glycolicacid), ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylenecarbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylenecarbonate, δ-valerolactone, β-butyrolactone, γ-butyrolactone,ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one(including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione),1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels and blends thereof.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever treatment of kinasemediated disorders, particularly protein kinase or glycogen synthasekinase mediated disorders, is required for a subject in need thereof.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.7 mg to about 21,000 mg per70 kilogram (kg) adult human per day; preferably in the range of fromabout 7 mg to about 7,000 mg per adult human per day; and, morepreferably, in the range of from about 7 mg to about 2,100 mg per adulthuman per day. For oral administration, the compositions are preferablyprovided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe subject to be treated. A therapeutically effective amount of thedrug is ordinarily supplied at a dosage level of from about 0.01 mg/kgto about 300 mg/kg of body weight per day. Preferably, the range is fromabout 0.1 mg/kg to about 100 mg/kg of body weight per day; and, mostpreferably, from about 0.1 mg/kg to about 30 mg/kg of body weight perday. Advantageously, compounds of the present invention may beadministered in a single daily dose or the total daily dosage may beadministered in divided doses of two, three or four times daily.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease condition. In addition, factors associatedwith the particular subject being treated, including subject age,weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

ATP = adenosinetriphosphate BSA = bovine serum albumin DCM =dichloromethane DMF = N,N-dimethylformamide DMSO = dimethylsulfoxideEDTA = ethylenediaminetetraacetic acid EGTA =ethylenebis(oxyethylenenitrilo)tetraacetic acid h = hour HEPES =4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid min = minute NT =not tested rt = room temperature TBAF = tert-butylammonium fluoride TCA= trichloroacetic acid THF = tetrahydrofuran TFA = trifluoroacetic acidSEM = 2-(trimethylsilyl)ethoxymethyl

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The following schemes describe general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared.

Additional representative compounds of the present invention can besynthesized using the intermediates prepared in accordance with theschemes and other materials, compounds and reagents known to thoseskilled in the art.

In Scheme AA, the 7-azaindole Compound AA1 (optionally substituted withR³) was treated with ethylmagnesium bromide followed by alkylation with(C₁₋₂)alkylchlorooxoacetate to give Compound AA2.

Compound AA2 was then alkylated with an appropriate alkylating agent inthe presence of a base such as cesium or potassium carbonate in adipolar aprotic solvent such as DMF to give Compound AA3 (wherein R¹ wasa substituted or unsubstituted alkyl group).

The glyoxylate ester Compound AA3 was then reacted with an acetamideCompound AA4 (substituted with R(R₂,R₄); wherein the “R” group isselected from cycloalkyl, heterocyclyl, aryl and heteroaryl; and, ispreferably selected from an aromatic, heteroaromatic or partiallysaturated heterocyclic ring system) stirred in an aprotic solvent suchas THF with ice bath cooling and a base, such as potassium tert-butoxideor sodium hydride, to give a target Compound AA5.

Alternatively, in Scheme AB, Compound AA1 was treated with anappropriate alkylating agent under basic conditions (wherein R¹ was asubstituted or unsubstituted alkyl group), or an appropriate aryl orheteroaryl halide in the presence of a base such as cesium or potassiumcarbonate and copper oxide in a dipolar aprotic solvent such as DMF(wherein R¹ was a substituted or unsubstituted aryl or heteroaryl group)to give Compound AB1. Acylation of AB1 with oxalyl chloride in anaprotic solvent such as diethyl ether or DCM followed by addition ofmethanol or sodium methoxide afforded Compound AA3.

In Scheme AC, the 7-azaindole Compound AC1 (optionally substituted withR³) was reacted with a halogenated R¹ group (optionally protected with asuitable protecting group) to give Compound AC2. The pyrrolinylenemoiety on Compound AC4 was then synthesized via Compound AC3 and wasconverted to the chloride or —OSO₂CF₃ (triflate) substituted CompoundAC5. Using a palladium-catalyzed cross-coupling reaction, Compound AC5was reacted with an organometallic species (such as organotin,organoboron, organozinc, organosilicon, organocopper, organomagnesium,etc.) in the presence of a ligand (such as triphenylphosphine,triphenylarsine, etc) to give Compound AA5.

Specific Synthetic Methods

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The depicted intermediates may alsobe used in subsequent examples to produce additional compounds of thepresent invention. No attempt has been made to optimize the yieldsobtained in any of the reactions. One skilled in the art would know howto increase such yields through routine variations in reaction times,temperatures, solvents and/or reagents.

All chemicals were obtained from commercial suppliers and used withoutfurther purification. ¹H and ¹³C NMR spectra were recorded on a BrukerAC 300B (300 MHz proton) or a Bruker AM-400 (400 MHz proton)spectrometer with Me₄Si as an internal standard (s=singlet, d=doublet,t=triplet, br=broad). APCI-MS and ES-MS were recorded on a VG PlatformII mass spectrometer; methane was used for chemical ionization, unlessnoted otherwise. Accurate mass measurements were obtained by using a VGZAB 2-SE spectrometer in the FAB mode. TLC was performed with Whatman250-μm silica gel plates. Preparative TLC was performed with Analtech1000-μm silica gel GF plates. Flash column chromatography was conductedwith flash column silica gel (40–63 μm) and column chromatography wasconducted with standard silica gel. HPLC separations were carried out onthree Waters PrepPak® Cartridges (25×100 mm, Bondapak® C18, 15–20 μm,125 Å) connected in series; detection was at 254 nm on a Waters 486 UVdetector. Analytical HPLC was carried out on a Supelcosil ABZ+PLUScolumn (5 cm×2.1 mm), with detection at 254 nm on a Hewlett Packard 1100UV detector. Microanalysis was performed by Robertson MicrolitLaboratories, Inc.

Compounds are named according to nomenclature conventions well known inthe art or, as in the compound names for the examples presented, may begenerated using commercial chemical naming software such as theACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario).

EXAMPLE 13-(2-chlorophenyl)-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 1)

Ethylmagnesium bromide in diethyl ether (3.0 M, 63 mL) was addeddropwise to a solution of Compound 1a (20 g, 0.156 mole) in THF (300 mL)cooled in an ice bath. The resulting yellowish mixture of solids wasstirred at 65° C. for 1 h, then cooled with an acetone-dry ice bath. Asolution of methyl chlorooxoacetate (47.66 g) in THF (40 mL) was addeddropwise to the cooled mixture. The cooled temperature was maintainedwhile the mixture was stirred for 30 min. The temperature was warmed upto 0° C. while the mixture was stirred for another 30 min at 0° C. Thereaction was quenched with saturated NH₄Cl (200 mL) and water (100 mL),then the mixture was filtered and the filtrate extracted with ethylacetate (2×500 mL). The organic layers were combined and washed withsaturated NaHCO₃ (2×250 mL), brine (250 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to give 7.64 g (24%) of Compound 1b asa yellow solid. Compound 1b, without further purification, was directlyused in the next step. ¹H NMR (CDCl₃) δ 8.78 (dd, J=1.5, 7.9 Hz, 1H),8.75 (s, 1H), 8.47 (dd, J=1.5, 4.9 Hz, 1H), 7.37 (dd, J=4.9, 7.9 Hz, 1H)3.99 (s, 1H). ES-MS m/z 205 (MH⁺).

A mixture of crude Compound 1b (4.0 g, 19.6 mmol) and cesium carbonate(8.298 g, 25.5 mmol) in anhydrous DMF (100 mL) was stirred undernitrogen at 50° C. for one hour, then was treated with(3-bromopropoxy)-tert-butyl-dimethylsilane (4.96 g, 19.6 mmol). Thestirring was continued at 50° C. for 5 h. The reaction mixture was thendiluted with ethyl acetate (500 mL) and washed with brine (2×100 mL).The organic layer was separated, dried over anhydrous sodium sulfate andconcentrated in vacuo. This crude product was purified by flashchromatography on silica (EtOAc/hexane, from 1:7 to 1:4) to giveCompound 1c (2.1 g). ¹H NMR (CDCl₃) δ 8.6 (m, 1H), 8.47 (s, 1H),7.27–7.22 (m, 1H), 4.46–4.41 (t, 2H), 3.9 (s, 3H), 3.58–3.54 (t, 2H),2.12–2.04 (m, 2H), 0.87 (s, 9H), 0 (s, 6H). ES-MS m/z 377 (MH⁺).

A mixture of Compound 1c (322 mg, 0.857 mmol) and Compound 1d (121 mg,0.714 mmol) in 7 mL of anhydrous THF was stirred under nitrogen andcooled in an ice bath while treating dropwise with 2.9 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred for 30 minutes inan ice bath then at room temperature for another 30 min. The reddishmixture was then cooled down and then 2 mL of concentrated HCl was addeddropwise. The mixture was stirred for 5 min. Ethyl acetate (150 mL) andH₂O (30 mL) were added. The organic layer was separated and washed withsaturated NaHCO₃ and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was separated by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 98:2:0.2 to95:5:0.5) to yield 150 mg (55%) of Compound 1 as a yellow solid. ¹H NMR(CDCl₃) δ 8.21 (dd, J=1.5, 4.7 Hz, 1H), 8.17 (s, 1H), 7.48–7.33 (m, 4H),6.78 (dd, J=4.7, 8.1 Hz, 1H), 6.66 (dd, J=1.5, 8.1 Hz, 1H), 4.5 (dd,J=2.6, 7.1 Hz, 2H), 3.41 (t, J=5.5 Hz, 2H), 2.03 (m, 2H). ES-MS m/z 382(MH⁺).

Using the procedure of Example 1 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 53-(5-chlorobenzo[b]thien-3-yl)-4-[1-(3-hydroxypropyl)- 4381H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 63-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4- 388(1H-indazol-3-yl)-1H-pyrrole-2,5-dione 103-(2-chloro-4-fluorophenyl)-4-[1-(3-hydroxypropyl)-1H- 400pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 113-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4- 416[2-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione 123-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4- 349(2-pyridinyl)-1H-pyrrole-2,5-dione 133-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-[1-(3- 451hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H- pyrrole-2,5-dione 143-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4- 354(2-thienyl)-1H-pyrrole-2,5-dione 153-(2,5-dichloro-3-thienyl)-4-[1-(3-hydroxypropyl)-1H- 422pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 303-(2-hydroxyphenyl)-4-[1-(3-methoxypropyl)-1H- 378pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 313-(3,4-dimethoxyphenyl)-4-[1-(3-methoxypropyl)-1H- 422pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 323-(3,4-dihydroxyphenyl)-4-[1-(3-hydroxypropyl)-1H- 380pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 23-(2-chlorophenyl)-4-[1-[3-(dimethylamino)propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 2)

To a solution of Compound 1 (45 mg, 0.118 mmol) in THF (5 mL) was addedpyridine (41 mg, 0.5 mmol). The mixture was stirred at room temperaturefor 15 min and then methanesulfonic anhydride (65 mg, 0.37 mmol) wasadded and the mixture was heated to 50° C. for 2 h. TLC and mass spectrashowed the formation of Compound 2a. To the crude product was addedexcess 1.0 M solution of dimethylamine in THF (1 mL). The mixture washeated from 50 to 65° C. overnight. The solvent was concentrated invacuo. The crude product was extracted with ethyl acetate (100 mL). Theorganic phase was washed with saturated NaHCO₃, brine, and evaporated invacuo to give a crude product (50 mg). The crude product was separatedby flash chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 98:2:0.2to 95:5:0.5) to give 15 mg (31%) of Compound 2 as a yellow solid. ¹H NMR(DMSO-d₆) δ 8.27 (s, 1H), 8.23 (m, 1H), 7.44–7.33 (m, 4H), 6.75–6.71 (m,1H), 6.62–6.60 (m, 1H), 4.41–4.38 (m, 2H), 2.3–2.28 (m, 2H), 2.25 (s,6H), 2.12–2.05 (m, 2H). ES-MS m/z 409 (MH⁺).

Using the procedures of Examples 1 and 2 and the appropriate reagentsand starting materials known to those skilled in the art, othercompounds of the present invention may be prepared including, but notlimited to:

ES-MS m/z Cpd Name (MH⁺) 383-(2-methoxyphenyl)-4-[1-[3-(1H-tetrazol-1-yl)propyl]- 4301H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione 393-(2-methoxyphenyl)-4-[1-[3-(2H-tetrazol-2-yl)propyl]- 4301H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 33-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-naphthalenyl)-1H-pyrrole-2,5-dione(Compound 3)

A mixture of Compound 1c (406 mg, 1.08 mmol) and Compound 3a (154 mg,0.83 mmol) in 6 mL of anhydrous THF was stirred under nitrogen andcooled in an ice bath while treating dropwise with 4.2 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred for 30 minutes inan ice bath then at room temperature for another 30 min. The reddishmixture was then cooled down and then 2 mL of concentrated HCl was addeddropwise. The mixture was stirred for 5 min and then ethyl acetate (250mL) and H₂O (50 mL) were added. The organic layer was separated andwashed with saturated NaHCO₃ and brine, dried over anhydrous sodiumsulfate and concentrated in vacuo to give a crude product (0.45 g). Thecrude product was separated by flash chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, from 98:2:0.2 to 95:5:0.5) to give 203.8 mg (48%) ofCompound 3 as a yellow solid. ¹H NMR (DMSO-d₆) δ 8.23 (s, 1H), 8.05 (d,J=6.1 Hz, 2H), 7.97 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.61–7.53(m, 2H), 7.45 (t, J=7.4 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 6.52 (dd,J=4.7, 8.0 Hz, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.35 (t, J=6.9 Hz, 2H), 3.34(t, J=6.1 Hz, 2H), 1.88 (m, 2H). ES-MS m/z 398 (MH⁺). Anal. Calcd forC₂₄H₁₉N₃O₃: C, 72.54; H, 4.82; N, 10.58. Found: C, 72.29; H, 4.88; N,10.70.

EXAMPLE 43-[1-[3-(dimethylamino)propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-naphthalenyl)-1H-pyrrole-2,5-dione(Compound 4)

To a solution of Compound 3 (25 mg, 0.063 mmol) in THF (5 mL) was addedpyridine (24.9 mg, 0.315 mmol). The mixture was stirred at roomtemperature for 15 min and then methanesulfonic anhydride (43.9 mg, 0.25mmol) was added and the mixture was heated to 50° C. for 2 h. TLC andmass spectra shown the formation of Compound 4a. To the crude productwas added excess 1.0 M solution of dimethylamine in THF (1 mL). Themixture was heated from 50 to 65° C. overnight. The solvent wasconcentrated in vacuo. The crude product was extracted with ethylacetate (100 mL). The organic phase was washed with saturated NaHCO₃,brine, and evaporated in vacuo to give a crude product (50 mg). Thecrude product was separated by flash chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, from 98:2:0.2 to 95:5:0.5) to give 6 mg (22%) ofCompound 4 as a yellow solid. ¹H NMR (CDCl₃) δ 8.33 (s, 1H), 8.08 (dd,J=1.5, 4.7 Hz, 1H), 7.94 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.3Hz, 1H), 7.54 (m, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.28 (m, 1H), 6.44 (dd,J=4.7, 8.1 Hz, 1H), 6.26 (dd, J=1.5, 8.0 Hz, 1H), 4.37 (t, J=7.1 Hz,2H), 2.29 (t, J=7.0 Hz, 2H), 2.25 (s, 6H), 2.07 (m, 2H). ES-MS m/z 425(MH⁺).

EXAMPLE 53-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 7)

A mixture of Compound 1b (1.02 g) of and cesium carbonate (2.18 g, 6.5mmol) in anhydrous DMF (20 mL) was stirred under argon at 50° C. for 5min, then was treated with EtI (0.78 g, 5.0 mmol). The reaction mixturewas stirred at 50° C. for 40 min, then diluted with EtOAc (120 mL). Thsolution was washed with H₂O (2×30 mL), brine (30 mL), dried overanhydrous sodium sulfate, and concentrated in vacuo to give Compound 5a(0.80 g) as a viscous brown solid. ES-MS m/z 233 (MH⁺). To a solution ofCompound 5a (372 mg) in trifluoroacetic acid (15 mL) was addedtriethylsilane (1.86 g, 16.0 mmol) in one portion. The reaction mixturewas stirred at 55° C. for 18H. The volatiles were removed under vacuoand the residue was dissolved in EtOAc (80 mL). The solution was washedwith saturated NaHCO₃ (30 mL), brine (30 mL), dried over anhydroussodium sulfate, and concentrated in vacuo to give Compound 5b (313 mg)as a viscous brown solid. ES-MS m/z 219 (MH⁺).

A solution (in a pressure tube) of Compound 5b (218 mg) in 2.0 M ammoniain MeOH (8 mL) was stirred at 90° C. for 72H. The volatiles were removedunder vacuo and the residue was purified by flash column chromatography(CH₂Cl₂/MeOH/NH₄OH, 95:4.5:0.5) to afford Compound 5c (110 mg) as alight brown solid. ¹H NMR (CD₃OD) δ 8.22 (m, 1H), 8.02 (dd, J=7.9, 1.4Hz, 1H), 7.36 (s, 1H), 7.10 (dd, J=7.9, 4.8 Hz, 1H), 4.30 (q, J=7.2 Hz,2H), 3.65 (s, 2H), 1.43 (t, J=7.2 Hz, 3H). ES-MS m/z 204 (MH⁺). Amixture of Compound 5c (60 mg, 0.295 mmol) and Compound 1c (156 mg,0.413 mmol) in anhydrous THF (2 mL) was stirred under argon and cooledin an ice bath while treating dropwise with 1.0 M potassium t-butoxidein THF (1.2 mL, 1.2 mmol). The reaction mixture was stirred for 1 h inan ice bath then at rt for 1 h. To the dark reaction mixture cooled withan ice bath was added dropwise concentrated HCl (3 mL). The mixture wasstirred at rt for 5 min and then diluted with H₂O (30 mL), basified with6 N aqueous NaOH to pH=10. The solution was extracted with EtOAc (2×40mL). The combined extracts were washed with, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn chromatography (CH₂Cl₂/MeOH/NH₄OH, 93:6:1) to afford Compound 7(48 mg, 39% yield) as a red-orange solid. ¹H NMR (CDCl₃) δ 8.22 (m, 2H),7.92 (s, 1H), 7.76 (s, 1H), 7.32 (dd, J=8.0, 1.5 Hz, 1H), 7.08 (dd,J=8.0, 1.5 Hz, 1H), 6.81 (dd, J=8.1, 4.8 Hz, 1H), 6.70 (dd, J=8.0, 4.6Hz, 1H), 4.50–4.37 (m, 4H), 3.42 (m, 2H), 1.97 (m, 2H), 1.53 (t, J=7.3Hz, 3H). ES-MS m/z 416 (MH⁺).

EXAMPLE 63-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione(Compound 8)

A mixture of Compound 1c (196.3 mg, 0.520 mmol) and Compound 6a (66.25mg, 0.40 mmol) in 5 mL of anhydrous THF was stirred under nitrogen andcooled in an ice bath while treating dropwise with 1.7 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred for 30 minutes inan ice bath then at room temperature for another 30 min. The reddishmixture was then cooled down and then 2 mL of concentrated HCl was addeddropwise. The mixture was stirred for 5 min. Ethyl acetate (150 mL) andH₂O (30 mL) were added. The organic layer was separated and washed withsaturated NaHCO₃ and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was separated by reverse-phaseHPLC to give Compound 8 (35 mg, 14%) as a TFA salt, yellow solid. ¹H NMR(DMSO-d₆) δ 8.19 (m, 2H), 7.43 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.6 Hz,1H), 7.02 (m, 2H), 6.77 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.38 (m, 2H),3.40 (t, J=6.1 Hz, 2H), 3.30 (s, 3H), 1.95 (m, 2H). ES-MS m/z 378 (MH⁺).

EXAMPLE 73-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(3-methoxyphenyl)-1H-pyrrole-2,5-dione(Compound 9)

A mixture of Compound 1c (203.4 mg, 0.54 mmol) and Compound 6a (68.64mg, 0.416 mmol) in 5 mL of anhydrous THF was stirred under nitrogen andcooled in an ice bath while treating dropwise with 1.7 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred for 30 minutes inan ice bath then at room temperature for another 30 min. The reddishmixture was then cooled down and then 2 mL of concentrated HCl was addeddropwise. The mixture was stirred for 5 min. Ethyl acetate (150 mL) andH₂O (30 mL) were added. The organic layer was separated and washed withsaturated NaHCO₃ and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was separated by Gilson to giveCompound 9 (50 mg, 19.3%) as a TFA salt, yellow solid. ¹H NMR (CD₃OD) δ8.19 (m, 2H), 7.24 (t, J=7.4 Hz, 1H), 7.02 (m, 2H), 6.94 (d, J=8.0 Hz,1H), 6.85 (m, 2H), 4.48 (t, J=6.8 Hz, 2H), 3.62 (s, 3H), 3.57 (t, J=6.1Hz, 2H), 2.1 (m, 2H). ES-MS m/z 378 (MH⁺). Anal. Calcd forC₂₁H₁₉N₃O₄.0.85TFA-0.37H₂O: C, 56.69; H, 4.32; N, 8.74; F, 10.08; H₂O,1.39. Found: C, 56.72; H, 4.32; N, 9.04; F, 10.31; H₂O, 1.79.

EXAMPLE 83-[1-(3-hydroxypropyl)-1H-imidazol-4-yl]-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 18);3-[1-(2-hydroxyethyl)-1H-imidazol-4-yl]-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 19)

To prepare Compound 1c for use in this example, to a THF solution (20mL) of 7-azaindole Compound 1a (2.30 g, 19.5 mmol) was added EtMgBr(21.5 mmol, 1 M solution in THF), and the mixture was heated to gentlereflux for 1 h, and cooled to 20° C. Diethyl oxolate (8.0 mL, 58.5 mmol)was dissolved in THF (50 mL) and cooled to −40° C., and the freshlyprepared Grignard reagent was introduced slowly via a cannula. After theaddition was complete, the mixture was heated to 70° C. for 1.5 h, andcooled to 20° C. It was quenched with 5 mL of saturated NaHCO₃, anddiluted with water. The aqueous layer was extracted with EtOAc. Theorganic layers were combined, dried (MgSO₄) and concentrated. Theresidue was purified by flash chromatography on silica gel, elutinggradually with Hexane/EtOAc. 1.40 g was recovered and the desiredproduct Compound 1b was isolated as a pale yellow solid (1.0 g): ¹H NMR(300 MHz, CDCl₃) δ 11.8 (s, 1H), 8.75 (dd, J=7.9, 1.5 Hz, 1H), 8.70 (s,1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 7.35 (dd, J=7.9, 4.8 Hz, 1H), 4.44(q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H); MS (ES) m/z: 219 (M+H⁺). To amixture of Compound 1b (318 mg, 1.46 mmol) and Cs₂CO₃ (2.38 g, 7.30mmol) in DMF (5 mL) was added a DMF (2 mL) solution of(3-bromopropoxy)-tert-butyldimethylsilane (1.85 g, 7.30 mmol) at 80° C.After it was stirred at 80° C. for 10 min, the mixture was cooled,diluted with EtOAc, and filtered through celite. The filtrate was washedwith water (4×25 mL), dried (Na₂SO₄) and concentrated. The residue waschromatographed on silica gel, eluting gradually with Hexane/EtOAc. Thedesired product Compound 1c was isolated as a white crystalline solid(457 mg, 80%): ¹H NMR (300 MHz, CDCl₃) δ 8.61 (dd, J=6.3, 1.5 Hz, 1H),8.46 (s, 1H), 8.35 (dd, J=4.7, 1.5 Hz, 1H), 7.22 (m, 1H), 4.43 (t, J=6.8Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.57 (t, J=5.7 Hz, 2H), 2.05 (m, 2H),1.38 (t, J=7.1 Hz, 3H), 0.87 (s, 9H), 0.00 (s, 6H); MS (ES) m/z: 391(M+H⁺).

To prepare Compound 8b (where n=2), 1-H-4-imidazoleacetamide Compound 8a(115 mg, 0.92 mmol, prepared as described in Zimmerman, S. C.Tetrahedron, 1991, 47, 2649–2660) and Cs₂CO₃ (450 mg, 1.38 mmol) weremixed with DMF (2.0 mL), and (3-bromopropoxy)-tert-butyldimethylsilane(350 mg, 1.38 mmol) in a DMF (1.0 mL) solution was added. The resultingmixture was heated to 70° C. for 5.5 h, and it was then cooled to 20° C.The mixture was diluted with EtOAc and filtered through celite. Thefiltrate was washed with water, dried (Na₂SO₄) and concentrated in vacuoto give Compound 8b (where n=2) (100 mg) as a sticky yellow oil: ¹H NMR(300 MHz, CDCl₃) δ 7.38 (s, 1H), 6.70 (s, 1H), 3.98 (t, J=6.9 Hz, 2H),3.52 (t, J=5.6 Hz, 2H), 3.46 (s, 2H), 1.87 (m, 2H), 0.86 (s, 9H), 0.00(s, 6H); MS (ES) m/z: 298 (M+H⁺).

To prepare Compound 8b (where n=3), a DMF (1.0 mL) solution of(2-bromoethoxy)-tert-butyldimethylsilane (301 mg, 1.26 mmol) was addedto a mixture of 1-H-4-imidazoleacetamide Compound 8a (105 mg, 0.84mmol), Cs₂CO₃ (411 mg, 1.26 mmol) and DMF (2.0 mL). The mixture washeated to reflux for 5 h, and it was then cooled to 20° C. The mixturewas diluted with EtOAc and filtered through celite. The filtrate waswashed with water, dried (Na₂SO₄) and concentrated in vacuo to giveCompound 8b (where n=3) as an oil (149 mg, 63%): ¹H NMR (300 MHz, CDCl₃)δ 7.51 (s, 1H), 6.86 (s, 1H), 4.03 (t, J=4.7 Hz, 2H), 3.86 (t, J=4.8 Hz,2H), 3.54 (s, 2H), 0.89 (s, 9H), 0.00 (s, 6H); MS (ES) m/z: 284 (M+H⁺).

To prepare Compound 8c (where n=3), KOt-Bu (0.24 mmol, 1 M solution inTHF) at 0° C. was added to a THF (0.25 mL) solution of oxolate Compound1c (48 mg, 0.12 mmol) and imidazole Compound 8b (where n=3), (33 mg,0.11 mmol). After the mixture was stirred at 0° C. for 15 min, it waswarmed to 20° C. for 1 h. After the solvent was removed under reducedpressure, the residue was chromatographed on silica gel, eluting withHex/EtOAc to give Compound 8c (where n=3) as an orange red oil whichcrushed out in hexane as a fine yellow powder (32 mg): ¹H NMR (300 MHz,CDCl₃) δ 8.30 (dd, J=4.7, 1.3 Hz, 1H), 8.25 (s, 1H), 7.74 (s, 1H), 7.54(dd, J=8.0, 1.4 Hz, 1H), 7.44 (s, 1H), 6.96 (dd, J=8.0, 4.7 Hz, 1H),4.47 (t, J=7.0 Hz, 2H), 4.12 (t, J=6.8 Hz, 2H), 3.72 (t, J=5.8 Hz, 2H),3.60 (t, J=5.6 Hz, 2H), 2.14 (m, 2H), 1.98 (m, 2H), 0.92 (s, 9H), 0.91(s, 9H), 0.07 (s, 6H), 0.00 (s, 6H); MS (ES) m/z: 624 (M+H⁺).

To prepare Compound 8c (where n=2), KOt-Bu (1.20 mmol, 1 M in THF) at 0°C. was added to a THF (1.1 mL) solution of oxolate Compound 1c (234 mg,0.60 mmol) and imidazole Compound 8b (where n=2) (153 mg, 0.54 mmol).The mixture was stirred at 0° C. for 10 min, and then warmed to 20° C.for 1.5 h. It was concentrated and the resulting residue waschromatographed on silica gel, eluting with EtOAc/Hexane to give thedesired product Compound 8c (where n=2) (161 mg), which was crystallizedfrom hexane containing a small amount of EtOAc as a red chip: ¹H NMR(400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.29 (s, 1H), 8.24 (d, J=4.5 Hz,1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.00 (m, 1H),4.39 (t, J=7.1 Hz, 2H), 4.13 (t, J=4.3 Hz, 2H), 3.83 (t, J=4.5 Hz, 2H),3.64 (t, J=5.8 Hz, 2H), 2.03 (t, J=6.4 Hz, 2H), 0.87 (s, 9H), 0.81 (s,9H), 0.01 (s, 6H), −0.01 (s, 6H); MS (ES) m/z: 610 (M+H⁺).

A small amount of Compound 8d (32 mg, 10%) was also isolated in bothcases from the reaction mixture as an orange yellow solid: ¹H NMR (400MHz, CDCl₃) δ 8.30 (s, 1H), 8.23 (s, 1H), 7.70 (s, 1H), 7.53 (d, J=9.5Hz, 1H), 6.98 (m, 1H), 4.46 (t, J=7.0 Hz, 2H), 4.11 (t, J=5.0 Hz, 2H),3.89 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.8 Hz, 2H), 3.49 (s, 1H), 2.13 (m,2H), 0.91 (s, 9H), 0.06 (s, 6H); MS (ES) m/z: 496 (M+H⁺).

To prepare Compound 18, TBAF (0.40 mmol, 1 M solution in THF) at 20° C.was added to a THF (1.0 mL) solution of Compound 8c (where n=3) (84 mg,0.14 mmol). After the mixture was stirred for 30 min, the solvent wasremoved under reduced pressure. The residue was crystallized fromMeOH/EtOAc to give Compound 18 as an orange solid (55 mg): ¹H NMR (300MHz, DMSO-d₆) δ 10.9 (s, 1H), 8.33 (s, 1H), 8.25 (d, J=4.4 Hz, 1H), 7.84(s, 1H), 7.69 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.02 (m, 1H), 4.65 (s,1H), 4.64 (s, 1H), 4.39 (t, J=6.7 Hz, 2H), 4.10 (t, J=6.6 Hz, 2H), 3.47(d, J=5.8 Hz, 2H), 3.38 (d, J=5.5 Hz, 2H), 1.98 (t, J=6.2 Hz, 2H), 1.87(t, J=6.1 Hz, 2H); MS (ES) m/z: 396 (M+H⁺).

To prepare Compound 19, TBAF (0.31 mmol, 1 M in THF) at 20° C. was addedto a THF (1.0 mL) solution of Compound 8c (where n=2) (86 mg, 0.14mmol). The mixture was stirred at 20° C. for 2 h, and then concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with MeOH/CH₂Cl₂ to give Compound 19 (48 mg),which was crystallized from MeOH/EtOAc as an orange red solid: ¹H NMR(400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=4.3 Hz,1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.04 (dd,J=7.9, 4.6 Hz, 1H), 5.00 (t, J=5.1 Hz, 1H), 4.66 (d, J=4.6 Hz, 1H), 4.40(t, J=6.9 Hz, 2H), 4.08 (t, J=5.1 Hz, 2H), 3.68 (q, J=4.6 Hz, 2H), 3.48(d, J=4.9 Hz, 2H), 1.99 (m, 2H); MS (ES) m/z: 382 (M+H⁺).

EXAMPLE 93-[1-(3-hydroxypropyl)-1H-pyrazol-3-yl]-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 16)

To prepare Compound 1c for use in this example, ethyl magnesium bromidewas added dropwise to a THF solution (40 mL) of 7-azaindole Compound 1a(2 g, 16.9 mmol) at 0° C. The mixture was refluxed for 30 minutes,cooled to 23° C. then transferred via cannula to a THF solution (20 mL)of ethyl chloroacetate (6.2 mL, 55.77 mmol) at −78° C. over 1 hour. Themixture was then warmed to 23° C., refluxed for 1 hour, cooled to 23° C.and quenched with NaHCO₃. After extraction with EtOAc (3×50 mL), thecombined organic layers were dried (Na₂SO₄), filtered and concentrated.The product was purified by column chromatography (SiO₂) thenrecrystallized to give 1.9 g of Compound 1b as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 8.81 (dd, J=7.9, 1.5 Hz, 1H), 8.72 (s, 1H), 8.44 (dd,J=4.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9, 4.9 Hz, 1H), 4.47 (q, J=7.2 Hz,2H), 1.46 (t, J=7.2 Hz, 3H); MS (ES) m/z: 217 (M−H⁺). To a DMF solution(300 mL) of oxo-(1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid ethyl esterCompound 1b (1 g, 4.6 mmol) at 23° C. was added cesium carbonate (7.465g, 22.9 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (5.3 mL, 5.3mmol) under nitrogen. The resulting solution was warmed to 70° C. andstirred for 1 hour. After cooling the mixture was diluted with EtOAc (50mL), filtered through celite and washed with water (5×50 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresulting dark oil was purified (SiO₂) to give Compound 1c (0.827 g) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (dd, J=7.7, 1.5 Hz, 1H),8.50 (s, 1H), 8.40 (dd, J=4.7, 1.7 Hz, 1H), 7.3 (dd, J=7.9, 4.7 Hz, 1H),4.50 (t, J=6.8 Hz, 2H), 4.40 (q, J=7.4 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H),2.12 (m, J=5.8 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 0.91 (s, 9H), 0.03 (s,6H); MS (ES) m/z: 391 (M+H⁺).

To a DMF solution (4 mL) of 2-(1H-pyrazol-3-yl)-acetamide Compound 9a(0.2 g, 1.6 mmol; prepared as described in Jones, R. G., J. Am. Chem.Soc. 1953, 75, 4048) at 23° C. was added cesium carbonate (0.782 g, 2.4mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (0.608 g, 2.4 mmol)under nitrogen. The resulting solution was warmed to 70° C. and stirredfor 5 hours. After cooling the mixture was diluted with EtOAc (20 mL),filtered through celite and washed with water (5×10 mL). The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo. Theresulting yellow oil Compound 9b (0.5 g) was used without furtherpurification: ¹H NMR (400 MHz, CD₃OD) δ 7.50 (d, J=2.2 Hz, 1H), 6.20 (d,J=2.2 Hz, 1H), 4.18 (t, J=7 Hz, 2H), 3.59 (s, J=6 Hz, 2H), 3.51 (s, 2H),2.02 (m, J=6.2 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H); MS (ES) m/z: 298(M−H⁺). To a THF solution (0.4 mL) of2-[1-[3-(tert-butyldimethylsilanyloxy)propyl]-1H-pyrazol-3-yl]acetamideCompound 9b (0.147 g, 0.493 mmol) and[-[3-(tert-butyl-dimethylsilanyloxy)propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]oxo-aceticacid ethyl ester Compound 1c (0.214 g, 0.548 mmol) at 0° C. was addedpotassium tert-butoxide (1.1 mL, 1 M solution in THF, 1.1 mmol) dropwiseunder nitrogen. After 15 minutes the mixture was allowed to warm to 23°C. After partial concentration the crude product was purified by columnchromatography (SiO₂) to give 0.15 g of Compound 9c as a yellow oil: ¹HNMR (400 MHz, CDCl₃) δ 8.28 (m, 2H), 7.45 (d, J=2.2 Hz, 1H), 7.05 (dd,J=8.0, 1.4 Hz, 1H), 6.86 (dd, J=8.0, 1.4 Hz, 1H), 6.94 (dd, J=7.9, 4.6Hz, 1H), 6.74 (d, J=1.4 Hz, 1H), 4.45 (t, J=6.9 Hz, 2H), 4.13 (t, J=6.9Hz, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.49 (t, J=6.9 Hz, 2H), 2.14 (m, J=6.8Hz, 2H), 1.83 (m, J=6 Hz, 2H), 0.91 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H),0.01 (s, 6H); MS (ES) m/z: 624 (M+H⁺).

To prepare Compound 16, tert-butylammonium fluoride (0.303 mL, 1 Msolution in THF, 0.303 mmol) was added dropwise under nitrogen to a THFsolution (1 mL) of3-[1-[3-(tert-butyldimethylsilanyloxy)propyl]-1H-pyrazol-3-yl]-4-[1-[3-(tertbutyldimethylsilanyloxy)propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrrole-2,5-dioneCompound 9c (0.06 g, 0.096 mmol) at 23° C. After 2 hours the mixture wasconcentrated and the crude product was purified by column chromatography(SiO₂) to give 0.038 g of Compound 16 as a yellow oil: ¹H NMR (400 MHz,CD₃OD) δ 8.31 (s, 1H), 8.23 (dd, J=4.8, 2.2 Hz, 1H), 7.70 (d, J=2.2 Hz,1H), 7.15 (dd, J=8, 1.5 Hz, 1H), 6.98 (dd,J=8, 4.8 Hz, 1H), 6.70 (d,J=2.4 Hz, 1H), 4.47 (t, J=7 Hz, 2H), 4.16 (t, J=6.8 Hz, 2H), 3.6 (t,J=6.2 Hz, 2H), 3.45 (t, J=6 Hz, 2H), 2.11 (m, J=6.6 Hz, 2H), 1.86 (m,J=6.2 Hz, 2H); MS (ES) m/z: 396 (M+H⁺).

EXAMPLE 103-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1H-imidazol-2-yl)-1H-pyrrole-2,5-dione(Compound 17)

To a water solution (20 mL) of KCN (5.46 g, 83.9 mmol) at 0° C. wasadded 2-chloromethyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazoleCompound 10a (2.3 g, 9.32 mmol; prepared as described in Kania, S. L.,PCT Int. Appl. 2001, US18263) in EtOH (40 mL) dropwise. Once additionwas complete, the mixture was stirred at 23° C. for 4 hours. Thesolution was filtered and the precipitate washed with 95% EtOH (100 mL).The filtrate was then concentrated to small volume and water added (20mL). After extraction of the aqueous layer with CHCl₃ (4×50 mL) thecombined organic layers were concentrated to give a dark oil which waspurified by column chromatography (SiO₂) to give 0.813 g (40%) ofCompound 10b as a pale oil: ¹H NMR (300 MHz, CDCl₃) δ 6.95 (s, 2H), 5.26(s, 2H), 3.89 (s, 2H), 3.45 (br t, J=8.4 Hz, 2H), 0.87 (br t, J=8.4 Hz,2H), −0.06 (s, 9H); MS (ES) m/z: 260 (M+Na⁺).

To a DMSO solution (3 mL) of[1-(2-trimethylsilanylethoxymethyl)-1H-imidazol-2-yl]acetonitrile (0.813g, 3.4 mmol) Compound 10b at 0° C. was added K₂CO₃ (0.2 g, 1.7 mmol) inone portion followed by H₂O₂ (0.5 mL, 5.1 mmol) dropwise.

After 5 minutes MeOH (5 mL) was added and the mixture filtered,concentrated and the DMSO removed by a nitrogen stream. The productCompound 10c (0.648 g) was then obtained by recrystallization from Et₂Oas pale crystals: ¹H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 6.90 (s, 1H),5.37 (s, 2H), 3.77 (s, 2H), 3.53 (br t, J=7.9 Hz, 2H), 0.89 (br t, J=8.2Hz, 2H), −0.02 (s, 9H); MS (ES) m/z: 256 (M+H+). To a THF solution (0.4mL) of 2-[1-(2-trimethylsilanylethoxymethyl)-1H-imidazol-2-yl]acetamideCompound 10c (0.126 g, 0.493 mmol) andoxo-[1-(2-trimethylsilanylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]aceticacid ethyl ester Compound 1c (prepared according to the procedure ofExample 9; where the alkyl group is selected from ethyl) (0.214 g, 0.548mmol) at 0° C. was added potassium tert-butoxide (1.1 mL, 1 M solutionin THF, 1.1 mmol) dropwise under nitrogen. After 15 minutes the mixturewas allowed to warm to 23° C. and stirred for 30 minutes. The crudeproduct was then partially concentrated and purified by columnchromatography (SiO₂) to give 0.06 g of Compound 10d as a yellow oil: ¹HNMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.31 (m, 2H), 7.32 (m, 1H), 6.91(dd, J=8, 4.8 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 5.21 (s, 2H), 4.50 (t,J=6.8 Hz, 2H), 3.7 (t, J=5.7 Hz, 2H), 3.44 (br t, J=8.2 Hz, 2H), 2.15(m, J=6.2 Hz, 2H), 0.97 (s, 9H), 0.79 (br t, J=8.2 Hz, 2H), 0.12 (s,6H), −0.08 (s, 9H); MS (ES) m/z: 583 (M+H⁺).

To a CH₂Cl₂ solution (2 mL) of3-[1-[3-(tert-butyl-dimethylsilanyloxy)propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-[1-(2-trimethylsilanylethoxymethyl)-1H-imidazol-2-yl]pyrrole-2,5-dioneCompound 10d (0.048 g, 0.082 mmol) at 0° C. was added TFA (1 mL). After10 minutes toluene (5 mL) was added and the mixture was concentrated.The crude product was purified by column chromatography (SiO₂) to give0.004 g of Compound 12a as a yellow oil (see Example 12 forcharacterization of Compound 12a) and a mixture of Compound 12a andCompound 17. To a CH₂Cl₂ solution (1 mL) of the mixture of Compound 12aand Compound 17 (0.03 g) at 23° C. was added TFA (1 mL). After 20 hourstoluene (5 mL) was added and the mixture was concentrated. The crudeproduct was purified by column chromatography (SiO₂) to give 0.008 g ofCompound 17 as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H),8.24 (dd, J=4.8, 1.5 Hz, 1H), 7.28 (m, 2H), 7.12 (dd, J=8, 1.5 Hz, 1H),6.98 (dd, J=7.9, 4.6 Hz, 1H), 4.48 (t, J=6.8 Hz, 2H), 3.61 (t, J=6.2 Hz,2H), 2.10 (m, J=6.4 Hz, 2H); MS (ES) m/z: 338 (M+H⁺).

EXAMPLE 11 Intermediate Compound 11e and 11f

To a THF solution (2 mL) of (1H-[1,2,4]triazol-3-yl-acetic acid ethylester Compound 11a (0.1 g, 0.65 mmol; prepared as described in Jones, R.G., J. Am. Chem. Soc. 1954, 76, 5651) at 0° C. was added sodium hydride(0.034 g, 60% dispersion, 0.84 mmol) under nitrogen. After 30 minutes2-(trimethylsilyl)ethoxymethyl chloride (0.125 mL, 0.7 mmol) was added.Water (4 mL) was added after 2 hours and the THF was removed in vacuo.The residue was extracted with CHCl₃ (3×10 mL) and the organic layer wasdried (MgSO₄) and concentrated. The product Compound 11b (0.07 g) wasobtained as an oil without further purification: ¹H NMR (300 MHz, CD₃OD)δ 7.87 (s, 1H), 5.54 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.99 (s, 2H), 3.58(br t, J=8.3 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H), 0.91 (br t, J=8.5 Hz, 2H),0.00 (s, 9H); MS (ES) m/z: 284 (M−H⁺). A solution of Compound 11b (0.07g, 0.234 mmol) in ammonia (2 mL, 2 M in methanol) was stirred at 23° C.for 7 days. The solvent was then removed under vacuum giving 0.06 g(95%) of Compound 11c as a pale oil: ¹H NMR (300 MHz, CD₃OD) δ 7.81 (s,1H), 7.39 (s, 1H), 6.35 (s, 1H), 5.49 (s, 2H), 3.82 (s, 2H), 3.54 (br t,J=8.3 Hz, 2H), 0.85 (br t, J=8.5 Hz, 2H), −0.07 (s, 9H); MS (ES) m/z:279 (M+Na⁺).

To a THF solution (5 mL) of oxo-(1H-pyrrolo[2,3-b]pyridin-3-yl)aceticacid ethyl ester Compound 1b (prepared according to the procedure ofExample 9; where the alkyl group is selected from ethyl) (0.5 g, 2.29mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.764 g, 4.58 mmol)at 0° C. was added sodium hydride (0.11 g, 60% dispersion, 4.58 mmol)under nitrogen. After 24 hours water (4 mL) was added, the mixtureextracted with EtOAc (3×10 mL) and the organic layer dried (MgSO₄) andconcentrated. The product was purified by column chromatography (SiO₂)to give the product Compound 11d (0.224 g, 30%) as an oil: ¹H NMR (300MHz, CDCl₃) δ 8.65 (dd, J=7.9, 1.7 Hz, 1H), 8.61 (s, 1H), 8.41 (dd,J=4.7, 1.5 Hz, 1H), 7.27 (dd, J=7.9, 4.7 Hz, 1H), 5.71 (s, 2H), 4.40 (q,J=7.2 Hz, 2H), 3.60 (br t, J=8.3 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H), 0.91(br t, J=8.1 Hz, 2H), −0.09 (s, 9H); MS (ES) m/z: 371 (M+Na⁺).

To a THF solution (0.4 mL) of2-[1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,4]triazol-3-yl]acetamideCompound 11c (0.03 g, 0.116 mmol) andoxo-[1-(2-trimethylsilanylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]aceticacid ethyl ester Compound 1d (0.04 g, 0.116 mmol) at 0° C. was addedpotassium tert-butoxide (0.232 mL, 1 M solution in THF, 0.232 mmol)dropwise under nitrogen. After 15 minutes the mixture was allowed towarm to 23° C. and stirred for 1 hour. Conc. HCl (1 mL) was added andthe solution stirred for 5 minutes then poured into EtOAc (10 mL). Theaqueous layer was extracted with EtOAc (3×10 mL) then the organic layerwas dried (MgSO₄) and concentrated. The product was purified by columnchromatography (SiO₂) to give 0.017 g of Compound 11e as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 9.13 (s, 1H), 8.40 (dd, J=4.7, 1.5 Hz, 1H),8.10 (s, 1H), 8.00 (dd, J=8.1, 1.3 Hz, 1H), 7.18 (dd, J=8.1, 4.7 Hz,1H), 5.80 (s, 2H), 3.68 (br t, J=8.3 Hz, 2H), 0.96 (br t, J=8.3 Hz, 2H),−0.05 (s, 9H); MS (ES) m/z: 433 (M+Na⁺).

To a THF solution (0.4 mL) of2-[1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,4]triazol-3-yl]acetamideCompound 11c (0.03 g, 0.116 mmol) andoxo-[1-(2-trimethylsilanylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]aceticacid ethyl ester Compound 11d (0.04 g, 0.116 mmol) at 0° C. was addedpotassium tert-butoxide (0.232 mL, 1 M solution in THF, 0.232 mmol)dropwise under nitrogen. After 15 minutes the mixture was allowed towarm to 23° C. and stirred for 1 hour. Silica gel (1 g) was added andthe solution stirred for 5 minutes then EtOAc (10 mL) added and themixture filtered and concentrated. The product was purified by columnchromatography (SiO₂) then recrystallized to give 0.014 g (50%) ofCompound 11 f as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 1H),8.33 (dd, J=4.6, 1.3 Hz, 1H), 8.06 (s, 1H), 7.47 (s, 1H), 6.94 (dd,J=8.1, 4.8 Hz, 1H), 6.66 (dd, J=8.1, 1.5 Hz, 1H), 5.72 (s, 2H), 5.49 (s,2H), 3.62 (br t, J=8.2 Hz, 2H), 3.58 (br t, J=8.5 Hz, 2H), 0.95 (br t,J=8.4 Hz, 2H), 0.75 (br t, J=8.6 Hz, 2H), −0.04 (s, 9H), −0.09 (s, 9H);MS (ES) m/z: 539 (M−H⁺).

Other compounds of the invention may be obtained by substitutingIntermediate Compound 11e and Intermediate Compound 11f for Compounds10d, 9c or 8c in the reactions described for use thereof to providecompounds alkylated on the R₁ and R₂ positions.

EXAMPLE 12 Intermediate Compound 12a

Prepared by the method of Example 10, the crude product Compound 12a waspurified by column chromatography (SiO₂) as a yellow oil (0.004 g): ¹HNMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.24 (dd, J=4.8, 1.5 Hz, 1H), 7.45(d, J=1.3 Hz, 1H), 7.21 (d, J=1.3 Hz, 1H), 6.91 (dd, J=8, 4.8 Hz, 1H),6.58 (dd, J=8, 1.5 Hz, 1H), 5.22 (s, 2H), 4.48 (t, J=7 Hz, 2H), 3.57 (t,J=6 Hz, 2H), 3.42 (br t, J=8.2 Hz, 2H), 2.09 (m, J=6.4 Hz, 2H), 0.67 (brt, J=8.4 Hz, 2H), −0.15 (s, 9H); MS (ES) m/z: 468 (M+H⁺).

Other compounds of the invention may be obtained by substitutingIntermediate Compound 12a for Compounds 10d, 9c or 8c in the reactionsdescribed for use thereof to provide compounds alkylated on the R₂position.

EXAMPLE 133-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 20)

7-Azaindole Compound 1a (2.36 g, 20 mmol) and 2-bromonaphthalene (4.14g, 20 mmol) were dissolved in DMF (10 mL) and potassium carbonate (2.76g, 20 mmol) and CuO (300 mg, 3.6 mmol) were added in and the reactionwas refluxed under argon for 24 h. The reaction was cooled to roomtemperature and partitioned between DCM (100 mL) and water (100 mL). Theorganic layer was separated and the aqueous was extracted again with DCM(100 mL). The combined DCM solution was washed 3 times with water (50mL), twice with brine (50 mL), dried (Na₂SO₄) and evaporated in vacuo toa brown oil (3.92 g). This was purified via flash column chromatography(ethyl acetate/hexane 1:6) to give a white solid Compound 13a (2.15 g,44%). The indole Compound 13a (0.98 g, 4.0 mmol) in DCM (15 mL) wastreated with oxalyl chloride (0.52 g, 4.1 mmol) with ice bath coolingand then stirred at ambient temperature for 16 h. The reaction wascooled to 0° C. and a mixture of diisopropylethylamine-DIPEA (0.52 g,4.0 mmol) was added and the reaction was stirred at ambient temperaturefor 16 h. Again, the reaction was cooled to 0° C. and oxalyl chloride(125 mg, 1.0 mmol) was added and the reaction stirred at ambienttemperature for 24 h. The solution was cooled to −65° C. and sodiummethoxide (0.58 g, 10.0 mmol) in methanol (20 mL) was added in slowly,and the reaction was allowed to come to room temperature and stirred for1.5 h. The reaction was evaporated in vacuo to a solid, which wastriturated with chloroform (50 mL) for 30 min, filtered and the filtratedried (K₂CO₃) and evaporated in vacuo to a brown solid Compound 13b (1.0g), which was impure with starting material (20%) and DIPEA. ¹H NMR(CDCl₃) δ 4.00 (s, 3H), 7.38 (m, 1H), 7.58 (m, 2H), 7.95 (m, 4H), 8.21(s, 1H), 8.50 (m, 1H), 8.79 (m, 1H), 8.89 (s, 1H); ES-MS m/z 331 (MH⁺).

Indazole acid Compound 13c (5.28 g, 30 mmol) was dissolved in DCM (120mL) and DMF (30 mL) under argon and HOBT (4.45 g, 33 mmol) and DCC (6.51g, 32 mmol) were added and the reaction was stirred at ambienttemperature for 1 h. Ammonium hydroxide (28%, 2.7 g, 44 mmol) was addedover 5 min and the reaction was then stirred at ambient temperature for16 h. White solid was filtered and the filtrate diluted with DCM (150mL) and filtered again. The DCM solution was extracted four times with5% NaHCO₃ (150 mL); the combined aqueous solution was treated withsodium chloride (190 g) and extracted with ethyl acetate (300 mL) sixtimes. The organic extract was dried (Na₂SO₄) and evaporated in vacuo toa solid (6.25 g), which was triturated with diethyl ether (100 mL) andfiltered to afford a white solid Compound 13d (3.52 g, 67%). AmideCompound 13d (2.62 g, 15 mmol) in DMF (35 mL) was combined with3-dimethylaminopropylchloride hydrochloride (2.61 g, 16.5 mmol) and icebath cooled as 95% sodium hydride (0.80 g, 31.5 mmol) was addedportionwise over the next 20 min. The reaction was stirred at ambienttemperature for 10 min and then placed in an oilbath at 55° C. for 3 h.After cooling to room temperature, the reaction was diluted with DCM(200 mL) and washed with 0.3N NaOH (200 mL), twice with water (100 mL),brine (50 mL), dried (K₂CO₃) and evaporated in vacuo to a first crop oflight yellow solid (2.50 g). The aqueous solutions were re-extractedwith DCM (100 mL) three times and the DCM was washed with brine, dried(K₂CO₃) and evaporated in vacuo to give a second crop (1.63 g). Thesetwo crops were combined and purified by flash column chromatography(DCM:MeOH:NH₄OH in a ratio of 90:9:1) to afford a white solid Compound13e (2.63 g, 64%).

The ester Compound 13b (231 mg, 0.70 mmol) and amide Compound 13e (130mg, 0.50 mmol) were combined in dry THF (4 mL) under argon and cooledwith an ice bath as 1M potassium t-butoxide in THF (2.0 mL, 2.0 mmol)was added with stirring over the next 2 min. After stirring for 2 h at0° C., the reaction was quenched by slow addition of 12 M HCl (0.80 mL,9.6 mmol), stirred 15 min and then partitioned between chloroform andsaturated NaHCO₃. The organic solution was washed once with saturatedNaHCO₃, once with brine, dried (Na₂SO₄) and evaporated in vacuo to aflaky solid, which was purified by flash column chromatography(EA:MeOH:NH₄OH in a ratio of 80:8:2) to afford a flaky yellow solidCompound 20 (70 mg, 26%). This was dissolved in 20% MeOH in chloroform(10 mL) and 1N HCl in diethyl ether (0.30 mL, 0.30 mm) was added in; thesolution was evaporated in vacuo to the HCl salt, which was dissolved inwater (10 mL), frozen and lyophilized to an orange fluffy solid. ¹H NMR(CD₃OD) δ 2.35 (m, 2H), 2.86 (s, 6H), 3.29 (m, 2H), 4.65 (t, 2H, J=6.0Hz), 6.93 (dd, 1H, J=4.8, 8.0 Hz), 7.04 (dd, 1H, J=7.5, 7.7 Hz), 7.16(m, 1H), 7.5 (m, 5H), 8.15 (m, 6H), 8.50 (s, 1H). ES-MS m/z 541 (MH⁺).

Using the procedure of Example 13 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS Cpd Name m/z (MH⁺) 213-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-4-[1-(2- 513naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H- pyrrole-2,5-dione 333-(2-methoxyphenyl)-4-[1-(2-naphthalenyl)-1H- 446pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 143-[(E)-2-(4-fluorophenyl)ethenyl]-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 22)

Cesium carbonate (53.48 g, 164.15 mmol) and(3-Bromopropoxy)-tert-butyldimethylsilane (38.14 mL, 164.15 mmol) wereadded to a DMF solution (100 mL) of a(1H-Pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile Compound 14a (8.6 g, 54.7mmol; prepared as described in Robison, J. Amer. Chem. Soc., 78, 1956,1247–1249) and the resulting mixture was stirred at 90° C. After 1 hourthe reaction mixture was allowed to cool to 23° C. then filtered throughcelite, diluted with EtOAc (100 mL) and washed with water (5×100 mL).The organic layer was then dried (MgSO₄) and concentrated. The productwas purified by column chromatography (SiO₂) to give Compound 14b(16.465 g, 92%) as a pale oil. ¹H NMR (300 MHz, CDCl₃) δ 8.36 (dd,J=4.5, 1.3 Hz, 1H), 7.91 (dd, J=7.9, 1.5 Hz, 1H), 7.28 (s, 1H), 7.11(dd, J=7.9, 4.7 Hz, 1H), 4.38 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.60 (t,J=5.8 Hz, 2H), 2.06 (m, 2H), 0.93 (s, 9H), 0.05 (s, 6H); MS (ES) m/z:330 (M+H⁺). K₂CO₃ (0.34 g, 2.46 mmol) was added to a solution ofCompound 14b (1.6 g, 4.9 mmol) in DMSO (2.5 mL) at 0° C., followed byH₂O₂ (0.84 mL, 7.38 mmol, 30% solution in H₂O) added dropwise. Theresulting solution was stirred for 5 mins and EtOAc (50 mL) was added.The organic layer was washed with water (5×50 mL), dried (MgSO₄) andconcentrated. The product was purified by column chromatography (SiO₂)to give Compound 14c (1.43 g, 85%) as a pale oil. ¹H NMR (300 MHz,CD₃OD) δ 8.21 (d, J=4.1 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.32 (s, 1H),7.11 (dd, J=7.9, 4.9 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 3.61 (m, 4H), 2.03(m, 2H), 0.9 (s, 9H), 0.02 (s, 6H); MS (ES) m/z: 348 (M+H⁺).

Potassium tert-butoxide (0.99 mL, 1 M solution in THF, 0.99 mmol) wasadded dropwise under nitrogen to a THF solution (1 mL) of Compound 14c(0.173 g, 0.49 mmol) at 0° C. The mixture was stirred for 1 hour,concentrated and then purified by column chromatography (SiO₂) to giveCompound 14d (0.14 g, 70%) as a red oil. ¹H NMR (400 MHz, CD₃OD) δ 8.78(d, J=7.9 Hz, 1H), 8.13 (d, J=3.7 Hz, 1H), 7.83 (s, 1H), 6.99 (dd,J=7.9, 4.8 Hz, 1H), 4.32 (t, J=6.8 Hz, 2H), 3.58 (t, J=6.0 Hz, 2H), 2.00(m, 2H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES) m/z: 402 (M+H⁺). Sodiumhydride (0.105 g, 60% dispersion, 4.38 mmol) under nitrogen was added toa solution of Compound 14d (0.8 g, 1.99 mmol) at 0° C. in DMF (20 mL).After 30 minutes, the reaction was warmed to 23° C. and stirred for 1.5hours then recooled to 0° C. Iodomethane (1.35 mL, 2.19 mmol) was addedand the mixture stirred for 3 hours at 23° C. After being poured intoEtOAc (50 mL) the reaction mixture was washed with 1N HCl (25 mL). Theaqueous layer was then back-extracted with EtOAc (25 mL) and thecombined organic layers washed with brine (50 mL), dried (MgSO₄) andconcentrated. The product was purified by column chromatography (SiO₂)to give the product Compound 14e (0.77 g, 92%) as a red oil. ¹H NMR (300MHz, CDCl₃) δ 8.59 (d, J=7.4 Hz, 1H), 8.29 (d, J=3.8 Hz, 1H), 8.02 (s,1H), 7.04 (dd, J=7.4, 4.5 Hz, 1H), 4.40 (t, J=6.6 Hz, 2H), 3.61 (t,J=6.0 Hz, 2H), 3.04 (s, 3H), 2.07 (m, 2H), 0.89 (s, 9H), 0.03 (s, 6H);MS (ES) m/z: 416 (M+H⁺).

Triethylamine (0.64 mL, 4.62 mmol) was added to a solution of Compound14e (0.77 g, 1.85 mmol) in CH₂Cl₂ (10 mL) at −78° C. under nitrogenfollowed by (CF₃SO₂)₂O (triflic anhydride) (0.467 mL, 2.78 mmol) addeddropwise. After 1 hour, the CH₂Cl₂ was removed and EtOAc added. Themixture was then washed with water (4×20 mL), 0.1 N NaOH (20 mL) andbrine (20 mL), then dried (MgSO₄) and concentrated. The crude productwas purified by column chromatography (SiO₂) to give an intermediate(0.5 g, 54%) as a red oil. ¹H NMR (300 MHz, CDCl₃) δ 8.42 (dd, J=4.5,1.3 Hz, 1H), 8.30 (s, 1H), 8.22 (dd, J=8.1, 1.5 Hz, 1H), 7.23 (dd,J=8.1, 4.7 Hz, 1H), 4.50 (t, J=7.0 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.11(s, 3H), 2.11 (m, 2H), 0.89 (s, 9H), 0.02 (s, 6H); MS (ES) m/z: 548(M+H⁺). Trans-2-(4-Fluorophenyl)vinylboronic acid Compound 14f (0.015 g,0.09 mmol), Pd(OAc)₂ (0.002 g, 0.009 mmol) and KF (0.017 g, 0.3 mmol)were added to a solution of the red oil intermediate (0.05 g, 0.09 mmol)in THF (1 mL) at 23° C. A nitrogen atmosphere was then introduced andtricyclohexyl phosphine (3.8 mg in 50 μL THF, 0.014 mmol) was addeddropwise. After 30 minutes, ether (5 mL) was added and the mixture wasfiltered through celite and concentrated to give Compound 14g (0.046 g,96%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.38 (dd, J=4.7, 1.5 Hz,1H), 8.02 (dd, J=8.1, 1.7 Hz, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.86 (s,1H), 8.02 (m, 2H), 7.14 (m, 1H), 7.03 (m, 3H), 4.49 (t, J=7 Hz, 2H),3.69 (t, J=5.8 Hz, 2H), 3.11 (s, 3H), 2.15 (m, 2H), 0.87 (s, 9H), 0.04(s, 6H); MS (ES) m/z: 548 (M+H⁺).

Potassium hydroxide (10 N; 0.25 mL, 2.5 mmol) was added to a solution ofCompound 14g (0.045 g, 0.09 mmol) in EtOH (2 mL) at 23° C. The reactionwas stirred for 20 minutes, water (5 mL) was added and the mixture wasacidified with 2 drops of conc. HCl. After extraction with CH₂Cl₂ (3×10mL), the organic layers were dried (MgSO₄), filtered and concentrated invacuo. The resulting yellow oil Compound 14h (0.038 g, 77%) was usedwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.43 (dd, J=4.7,1.3 Hz, 1H), 8.07 (dd, J=8.1, 1.5 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J=16.4Hz, 1H), 7.48 (dd, J=8.7, 5.5 Hz, 1H), 7.20 (dd, J=8.1, 4.7 Hz, 2H),7.09 (m, 3H), 4.53 (t, J=6.8 Hz, 2H), 3.66 (t, J=5.8 Hz, 2H), 2.13 (m,2H), 0.88 (s, 9H), 0.04 (s, 6H); MS (ES) m/z: 507 (M+H⁺). Hexamethyldisilazine (0.146 mL, 0.65 mmol) in MeOH (0.5 mL) was added to asolution of Compound 14h (0.033 g, 0.065 mmol) in DMF (1 mL) at 23° C.The reaction was warmed to 80° C. and stirred for 6 hours then cooled to23° C. The mixture was purified (SiO₂) to give Compound 14i (0.020 g,63%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.41 (dd, J=4.7, 1.3 Hz,1H), 8.03 (dd, J=7.9, 1.3 Hz, 1H), 7.94 (m, 2H), 7.48 (m, 2H), 7.20 (m,2H), 7.01 (m, 2H), 4.52 (t, J=6.8 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.15(m, 2H), 0.88 (s, 9H), 0.05 (s, 6H); MS (ES) m/z: 506 (M+H⁺). TBAF (0.05mL, 1 M solution in THF, 0.05 mmol) was added dropwise to a solution ofCompound 14i (0.02 g, 0.041 mmol) in THF at 0° C. under nitrogen. After15 minutes the mixture was allowed to warm to 23° C. and stirred for 18hours. The crude product was concentrated and purified by columnchromatography (SiO₂) to give Compound 22 (0.015 g, 92%) as a yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 8.39 (d, J=4.1 Hz, 1H), 8.08 (d, J=7.9Hz, 1H), 7.93 (d, J=16.3 Hz, 1H), 7.84 (s, 1H), 7.45 (m, 2H), 7.19 (dd,J=8.1, 4.9 Hz, 1H), 7.04 (m, 3H), 4.55 (t, J=6 Hz, 2H), 3.48 (t, J=5.3Hz, 2H), 2.06 (m, 2H); MS (ES) m/z: 392 (M+H⁺).

EXAMPLE 153-(3,4-dihydro-2H-pyran-6-yl)-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 23)

Potassium carbonate (3.4 g, 24.7 mmol) was added to a solution of(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile Compound 14a (7.75 g, 49.4mmol; prepared as described in Robison, J. Amer. Chem. Soc., 78, 1956,1247–1249) in DMSO (15 mL) at 0° C., followed by dropwise addition ofhydrogen peroxide (8.4 mL, 74 mmol; 30% solution in H₂O). The resultingsolution was stirred for 10 mins, CH₂Cl₂ was added and the reactionmixture was then filtered and concentrated. CH₂Cl₂ (100 mL) was addedfollowed by Et₂O (20 mL) and the mixture cooled. The resultingprecipitate was filtered off to give Compound 15a (7.212 g, 84%) as ayellow solid. ¹H NMR (300 MHz, DMSO) δ 11.44 (br s, 1H), 8.19 (d, J=4.7,1.5 Hz, 1H), 7.95 (dd, J=7.9, 1.5 Hz, 1H), 7.39 (br s, 1H), 7.29 (s,1H), 7.06 (dd, J=7.9, 4.9 Hz, 1H), 6.86 (br s, 1H), 3.50 (s, 2H); MS(ES) m/z: 176 (M+H⁺). Cesium carbonate (0.45 g, 1.37 mmol) and(3-bromopropoxy)-tert-butyl-diphenyl-silane (0.19 g, 0.5 mmol) wereadded to a solution of 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetamideCompound 15a (0.08 g, 0.46 mmol) in DMF (2 mL) and the resulting mixturewas stirred at 70° C. After 6 h, the reaction mixture was filteredthrough celite, diluted with EtOAc (10 mL) and washed with water (5×10mL). The organic layer was then dried (MgSO₄) and concentrated. Thecrude product was purified by column chromatography (SiO₂) to giveCompound 15b (0.132 g, 60%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ8.31 (dd, J=4.6, 1.3 Hz, 1H), 7.85 (dd, J=4.6, 1.3 Hz, 1H), 7.64 (m,4H), 7.38 (m, 6H), 7.05 (m, 2H), 4.42 (t, J=6.6 Hz, 2H), 3.64 (t, J=5.9Hz, 2H), 3.62 (s, 2H), 2.09 (m, 2H), 1.08 (s, 9H); MS (ES) m/z: 472(M+H⁺).

Potassium tert-butoxide (0.69 mL, 0.69 mmol; 1 M solution in THF) wasadded dropwise to a solution of2-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-acetamideCompound 15b (0.13 g, 0.35 mmol) and diethyl oxalate (0.101 g, 0.69mmol) in TMF (2 mL) at 0° C. under nitrogen. After 20 minutes thereaction mixture was concentrated and a crude product was purified bycolumn chromatography (SiO₂) to give Compound 15c (0.117 g, 80%) as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ 9.44 (s, 1H), 8.69 (dd, J=7.9,1.3 Hz, 1H), 8.33 (dd, J=4.7, 1.5 Hz, 1H), 8.20 (s, 1H), 7.69 (m, 4H),7.41 (m, 6H), 7.14 (dd, J=7.9, 4.5 Hz, 1H), 4.6 (t, J=6.8 Hz, 2H), 3.73(t, J=6.0 Hz, 2H), 2.2 (m, 2H), 1.07 (s, 9H); MS (ES) m/z: 526 (M+H⁺).Oxalyl chloride (0.015 mL, 0.18 mmol) was added in one portion to asolution of3-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-hydroxy-pyrrole-2,5-dioneCompound 15c (0.03 g, 0.06 mmol) in 1:1 CH₂Cl₂/DMF (2 mL) at 23° C.under nitrogen. After one hour the reaction mixture was concentrated anda crude product was purified by column chromatography (SiO₂) to giveCompound 15d (0.023 g, 73%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ10.14 (s, 1H), 8.69 (dd, J=8.1, 1.5 Hz, 1H), 8.4 (dd, J=4.6, 1.5 Hz,1H), 8.36 (s, 1H), 7.67 (m, 4H), 7.41 (m, 6H), 7.25 (dd, J=8.1, 4.6 Hz,1H), 4.67 (t, J=6.8 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.24 (m, 2H), 1.04(s, 9H); MS (ES) m/z: 544 (M+H⁺).

Tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane Compound 15e (0.051 mL,0.13 mmol) was added to a solution of3-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), PdCl₂(PPh₃)₂ (0.007 g, 0.01 mmol) andlithium chloride (0.013 g, 0.3 mmol) in DMF (1.5 mL) at 23° C. undernitrogen. The reaction mixture was heated to 100° C. and stirred for 18h. After cooling to 23° C., the mixture was diluted with EtOAc (10 mL),washed with H₂O (3×10 mL), sat'd KF (1×10 mL) and brine (1×10 mL), thendried (MgSO₄) and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 15f (0.027 g, 46%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.34 (dd, J=4.7, 1.5 Hz, 1H), 7.96 (dd,J=8.7, 2.3 Hz, 1H), 7.93 (s, 1H), 7.66 (m, 4H), 7.38 (m, 6H), 7.13 (dd,J=7.9, 4.7 Hz, 1H), 5.78 (t, J=4.3 Hz, 2H), 4.52 (t, J=7.0 Hz, 2H), 3.83(m, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.29 (m, 2H), 2.16 (m, 2H), 1.86 (m,2H), 1.08 (s, 9H); MS (ES) m/z: 592 (M+H⁺). TBAF (0.07 mL, 0.07 mmol; 1M solution in THF) was added dropwise to a solution of3-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-(5,6-dihydro-4H-pyran-2-yl)-pyrrole-2,5-dioneCompound 15f (0.027 g, 0.046 mmol) in THF (2 mL) under nitrogen. After18 hours the mixture was concentrated and purified by columnchromatography (SiO₂) to give Compound 23 (0.011 g, 70%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=4.6 Hz, 1H), 7.99 (d, J=8.1Hz, 1H), 7.90 (s, 1H), 7.51 (br s, 1H), 7.18 (dd, J=7.9, 4.6 Hz, 1H),5.87 (t, J=4.2 Hz, 1H), 4.66 (m, 1H), 4.51 (t, J=6.0 Hz, 2H), 3.82 (t,J=4.9 Hz, 2H), 3.43 (m, 2H), 2.31 (m, 2H), 2.04 (m, 2H), 1.85 (m, 2H);MS (ES) m/z: 354 (M+H⁺).

Using the procedure of Example 15 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS Cpd Name m/z (MH⁺) 272,5-dihydro-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3- 296b]pyridin-3-yl]-2,5-dioxo-1H-pyrrole-3-carbonitrile

EXAMPLE 164-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[3,3′-bi-1H-pyrrole]-2,5-dione(Compound 24)

1-(Triisopropyl)pyrrole-3-boronic acid (0.053 mL, 0.2 mmol) was added toa solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol)and potassium fluoride (20 mg, 0.34 mmol)in THF (1 mL) at 23° C. under nitrogen. The mixture was stirred at 23°C. for 18 h, then diluted with EtOAc (10 mL), filtered through celiteand concentrated. The product was purified by column chromatography(SiO₂) to give Compound 16a (0.044 g, 60%) as a yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 8.28 (d, J=4.9 Hz, 1H), 7.74 (s, 1H), 7.66 (m, 4H),7.36 (m, 7H), 7.17 (m, 1H), 6.89 (dd, J=8.3, 4.9 Hz, 1H), 6.62 (m, 1H),6.37 (m, 1H), 4.53 (t, J=6.8 Hz, 2H), 3.7 (t, J=6.0 Hz, 2H), 2.2 (m,2H), 1.37 (sep, J=7.4 Hz, 3H),1.09 (s, 9H), 1.05 (s, 9H), 1.02 (s, 9H);MS (ES) m/z: 731 (M+H⁺).

TBAF (0.12 mL, 1 M solution in THF, 0.12 mmol) as added dropwise to asolution of3-benzofuran-2-yl-4-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dioneCompound 16a (0.044 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18hours the mixture was concentrated and purified by column chromatography(SiO₂) to give Compound 24 (0.017 g, 84%) as an orange solid. ¹H NMR(300 MHz, Acetone-d₆) δ 10.47 (s, 1H), 9.57 (s, 1H), 8.3 (dd, J=4.7, 1.5Hz, 1H), 7.9 (s, 1H), 7.56 (m, 1H), 7.49 (dd, J=7.9, 1.5 Hz, 1H), 7.01(dd, J=7.9, 4.7 Hz, 1H), 6.75 (m, 1H), 6.22 (m, 1H), 4.55 (t, J=6.6 Hz,2H), 4.02 (t, J=5.7 Hz, 1H), 3.56 (q, J=5.8 Hz, 2H), 2.11 (m, 2H); MS(ES) m/z: 388 (M+H⁺).

EXAMPLE 173-(2-benzofuranyl)-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 25)

2-Benzofuran boronic acid (0.032 mL, 0.2 mmol) was added to a solutionof3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol)and potassium fluoride (20 mg, 0.34 mmol)in THF (1 mL) at 23° C. under nitrogen. The reaction mixture was stirredat 23° C. for 18 h, diluted with EtOAc (10 mL), then filtered throughCelite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 17a (0.040 g, 64%) as a yellowsolid. ¹H NMR (300 MHz, Acetone-d₆) δ 8.34 (d, J=3.8 Hz, 1H), 8.26 (m,1H), 7.77 (m, 1H), 7.68 (m, 6H), 7.40 (m, 6H), 7.29 (m, 2H), 7.16 (m,1H), 7.13 (dd, J=8.1, 4.7 Hz, 1H), 4.69 (t, J=7.0 Hz, 2H), 3.83 (t,J=6.0 Hz, 2H), 2.3 (m, 2H), 1.06 (s, 9H); MS (ES) m/z: 626 (M+H⁺).

TBAF (0.1 mL, 0.1 mmol; 1 M solution in THF) was added dropwise to asolution of3-benzofuran-2-yl-4-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dioneCompound 17a (0.04 g, 0.064 mmol) in THF (1 mL) under nitrogen. After 18hours, the mixture was concentrated and purified by columnchromatography (SiO₂) to give Compound 25 (0.022 g, 89%) as an orangesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.32 (dd, J=4.7, 1.5Hz, 1H), 8.27 (s, 1H), 7.77 (m, 1H), 7.65 (s, 1H), 7.57 (dd, J=7.9, 1.3Hz, 1H), 7.29 (m, 3H), 7.02 (dd, J=7.9, 4.5 Hz, 1H), 4.47 (t, J=6.9 Hz,2H), 3.5 (t, J=6.0 Hz, 2H), 2.05 (m, 2H); MS (ES) m/z: 388 (M+H⁺).

EXAMPLE 183-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2,5-dione(Compound 26)

Cesium carbonate (3.5 g, 10.8 mmol) and iodomethane (0.51 g, 3.6 mmol)were added to a solution of 2-(1H-pyrazol-3-yl)-acetamide Compound 9a(0.45 g, 3.6 mmol) in DMF (5 mL) at 23° C. under nitrogen. The mixturewas warmed to 70° C. and stirred for 3 hours. After cooling, the mixturewas diluted with EtOAc (20 mL), filtered through celite and washed withwater (4×10 mL). The organic layer was dried (MgSO₄), filtered andconcentrated to give a first crude product (0.46 g) as a white solid. Bychromatography, the first crude product was shown to be a 2:1 mixture of2-(1-methyl-1H-pyrazol-3-yl)-acetamide and2-(2-methyl-2H-pyrazol-3-yl)-acetamide.

Potassium tert-butoxide (6.6 mL, 6.6 mmol; 1 M solution in THF) wasadded dropwise to a solution of the first crude product and Compound 1c(1.36 g, 3.47 mmol) in THF (20 mL) at 0° C. under nitrogen. Afterwarming to 23° C., the reaction was stirred for 2 h then concentratedand purified by column chromatography (SiO₂) to give a second crudeproduct (0.46 g) as a yellow solid which was then recrystallized(EtOAc/Hexanes) to give Compound 18a (0.36 g). ¹H NMR (400 MHz, CDCl₃) δ8.32 (s, 1H), 8.30 (dd, J=4.8, 1.7 Hz, 1H), 7.42 (d, J=2.2 Hz, 1H), 7.37(s, 1H), 7.09 (dd, J=7.9, 1.5 Hz, 1H), 6.93 (dd, J=7.9, 4.6 Hz, 1H),6.73 (d, J=2.2 Hz, 1H), 4.47 (t, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.71 (t,J=5.9 Hz, 2H), 2.15 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H); MS (ES) m/z:466 (M+H⁺).

TBAF (1.3 mL, 1 M solution in THF, 1.3 mmol) was added to a solution of3-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-methyl-1H-pyrazol-3-yl)-pyrrole-2,5-dioneCompound 18a (0.35 g, 0.75 mmol) in THF (15 mL) at 23° C. dropwise undernitrogen. After 18 hours, the mixture was concentrated and a crudeproduct was purified by column chromatography (SiO₂) (0.26 g, 98%) as ayellow solid. The crude product was then recrystallized (CH₂Cl₂:Hexane)to give Compound 26 (0.218 g). ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s,1H). 8.45 (s, 1H), 8.27 (dd, J=4.7, 1.5 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H),7.27 (dd, J=8, 1.5 Hz, 1H), 7.05 (dd, J=8.1, 4.7 Hz, 1H), 6.67 (d, J=2.3Hz, 1H), 4.4 (t, J=7 Hz, 2H), 3.79 (s, 3H), 3.46 (t, J=6 Hz, 2H), 1.99(m, 2H); MS (ES) m/z: 352 (M+H⁺).

EXAMPLE 193-dibenzo[b,d]thien-4-yl-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 28)

Dibenzothiophene-4-boronic acid (0.046 g, 0.2 mmol) was added to asolution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) and potassium fluoride (20 mg, 0.34mmol) in THF (1 mL) at 23° C. under nitrogen. The reaction mixture wasstirred at 23° C. for 18 h, then diluted with EtOAc (10 mL), filteredthrough celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 19a (0.039 g 56%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 8.23 (m, 2H), 8.1 (m, 2H), 7.63 (m,7H), 7.40 (m, 8H), 6.53 (m, 2H), 4.53 (m, 2H), 3.64 (m, 2H), 2.09 (m,2H), 1.10 (s, 9H); MS (ES) m/z: 692 (M+H⁺).

TBAF (0.85 mL, 0.085 mmol; 1 M solution in THF) was added dropwise to asolution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-dibenzothiophen-4-yl-pyrrole-2,5-dioneCompound 19a (0.039 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18hours the mixture was concentrated and purified by column chromatography(SiO₂) to give Compound 28 (0.017 g, 67%) as a yellow solid. ¹H NMR (300MHz, CD₃OD) δ 8.35 (dd, J=7.7, 1.5 Hz 1H), 8.25 (s, 1H), 8.21 (dd,J=6.8.3, 1.5 Hz, 1H), 8.01 (dd, J=4.7, 1.5 Hz, 1H), 7.68 (m, 3H), 7.39(m, 2H), 6.68 (dd, J=8.1, 1.5 Hz, 1H), 6.55 (dd, J=8.1, 4.7 Hz, 1H),4.42 (t, J=6.8 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 2.03 (m, 2H); MS (ES)m/z: 454 (M+H⁺).

EXAMPLE 203-(4-dibenzofuranyl)-4-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione(Compound 29)

Dibenzofuran-4-boronic acid (0.042 g, 0.2 mmol) was added to a solutionof3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) and potassium fluoride (20 mg, 0.34mmol) in THF (1 mL) at 23° C. under nitrogen. The reaction mixture wasstirred at 23° C. for 18 h, then diluted with EtOAc (10 mL), filteredthrough celite and concentrated. The crude product was purified bycolumn chromatography (SiO₂) to give Compound 20a (0.032 g, 48%) as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s, 1H), 8.05 (dd, J=4.0,2.3 Hz, 1H), 8.00 (dd, J=7.7, 1.1 Hz, 1H), 7.89 (m, 2H), 7.68 (m, 4H),7.61 (dd, J=5.6, 1.1 Hz, 1H), 7.29 (m, 7H), 7.24 (m, 1H), 7.05 (m, 1H),6.49 (m, 2H), 4.52 (t, J=6.8 Hz, 2H), 3.68 (t, J=5.7 Hz, 2H), 2.1 (m,2H), 1.11 (s, 9H); MS (ES) m/z: 676 (M+H⁺).

TBAF (0.7 mL, 0.06 mmol; 1 M solution in THF) was added dropwise to asolution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-dibenzofuran-4-yl-pyrrole-2,5-dioneCompound 20a (0.03 g, 0.04 mmol) in THF (1 mL) under nitrogen. After 18hours, the mixture was concentrated and purified by columnchromatography (SiO₂) to give Compound 29 (0.013 g, 71%) as a yellowsolid. ¹H NMR (300 MHz, Acetone-d₆) δ 8.28 (s, 1H), 8.18 (dd, J=7.7, 1.3Hz 1H), 8.02 (ddd, J=8.3, 4.5, 1.5 Hz, 2H), 7.74 (dd, J=7.5, 1.1 Hz,1H), 7.51 (m, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.64 (dd, J=7.9, 1.5 Hz,1H), 6.53 (dd, J=8.1, 4.7 Hz, 1H), 4.50 (t, J=6.6 Hz, 2H), 3.49 (m, 2H),2.04 (m, 2H); MS (ES) m/z: 438 (M+H⁺).

EXAMPLE 21[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]-carbamicacid 2-methylpropyl ester (Compound 34)

A mixture of crude Compound 1b (1.3 g, 6.4 mmol), 21a (2.29 g, 9.6 mmol)and cesium carbonate (2.09 g, 6.4 mmol) in anhydrous DMF (15 mL) wasstirred under nitrogen at 68° C. for 6 h. The solvent was evaporated.The residue was then diluted with ethyl acetate (250 mL) and washed withbrine (2×50 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated in vacuo to give 1.5 g of crude product21b.

A mixture of Compound 21b (200 mg, 0.55 mmol) and Compound 6a (63 mg,0.38 mmol) in 6 mL of anhydrous THF was stirred under nitrogen andcooled in an ice bath while treating dropwise with 1.9 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred for 30 minutes inan ice bath then at room temperature for another 30 min. The reddishmixture was then cooled down and then 2 mL of concentrated HCl was addeddropwise. The mixture was stirred for 5 min and then ethyl acetate (250mL) and H₂O (50 mL) were added. The organic layer was separated andwashed with saturated NaHCO₃ and brine, dried over anhydrous sodiumsulfate and concentrated in vacuo to give a crude oil, which wasseparated by flash chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from98:2:0.2 to 95:5:0.5) to give 78 mg (43%) of Compound 34 as a yellowsolid. ¹H NMR (CDCl₃) δ 8.23 (m, 1 H), 8.12 (s, 1 H), 7.99 (m, 1 H),7.40 (d, J=7.4 Hz, 1 H), 7.03 (m, 1 H), 6.86 (m, 1 H), 6.72 (m, 2 H),5.41 (m, 1 H), 4.41 (t, J=6.6 Hz, 2 H), 3.36 (s, 3 H), 3.05 (m, 2 H),2.06 (m, 2 H), 1.46 (s, 9H). ES-MS m/z 477 (MH⁺).

Using the procedure of Example 21 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 35[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H- 435pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]- carbamic acid methylester 36 [3-[3-[2,5-dihydro-4-(2-trifluoromethylphenyl)-2,5- 515dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1- yl]propyl]-carbamicacid 2-methylpropyl ester 37[3-[3-[2,5-dihydro-4-(2-trifluoromethylphenyl)-2,5- 473dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1- yl]propyl]-carbamicacid methyl ester

EXAMPLE 223-[1-(3-aminopropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione(Compound 38)

A solution of 20% TFA in CH₂Cl₂ was added to the compound 34. Themixture was stirred at room temperature overnight till no more startingmaterial. The solvent was evaporated and purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 98:2:0.2 to95:5:0.5) to give 100 mg (84%) of Compound 38 as a yellow solid. ¹H NMR(CDCl₃) δ 8.21 (m, 2 H), 7.40 (m, 2 H), 7.05 (m, 1 H), 6.85 (m, 1 H),6.69 (m, 2 H), 4.45 (t, J=6.9 Hz, 2 H), 3.33 (s, 3 H), 2.70 (t, J=6.5Hz, 2 H), 2.06 (m, 2 H). ES-MS m/z 377 (MH⁺).

EXAMPLE 23N-[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]-sulfamide(Compound 39)

To the mixture of compound 38 (50 mg, 0.133 mmol) in dioxane was addedlarge excess of sulfamide. The mixture was heated to 80° C. overnight.The solvent was evaporated and the residue was purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 99:1:0.1 to97:3:0.3) to give 10 mg (17%) of Compound 39 as a yellow solid. ¹H NMR(CD₃OD) δ 8.17 (m, 2 H), 7.42 (m, 1 H), 7.34 (d, J=6.0 Hz, 1 H), 7.00(m, 2 H), 6.75 (m, 2 H), 4.45 (t, J=6.9 Hz, 2 H), 3.36 (s, 3 H), 3.05(t, J=6.7 Hz, 2 H), 2.13 (t, J=6.8 Hz, 2 H). ES-MS m/z 456 (MH⁺).

EXAMPLE 244-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1′H-[3,3′]bipyrrolyl-2,5-dione(Compound 40)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (60 mg, 0.11 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added boronic acid derivative (0.2 mmol) at 23° C. undernitrogen. The reaction mixture was refluxed at 90° C. for 18 h. Uponcooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 40a (38 mg, 53%). ¹H NMR (300MHz, CDCl₃) δ 8.49 (s, 1 H), 8.29 (dd, J=4.71, 1.51 Hz, 1 H), 8.13 (s, 1H), 7.98 (s, 1 H), 7.67 (m, 4 H), 7.39 (m, 6 H), 7.00 (dd, J=7.91, 1.51Hz, 1 H), 6.87 (dd, J=8.10, 4.71 Hz, 1 H), 4.56 (m, 2 H), 4.04 (s, 3 H),3.69 (m, 2 H), 3.36 (s, 3 H), 2.17 (m, 2 H), 1.10 (s, 9 H); MS (ES) m/z:648 (M+H⁺).

To a solution of 40a (38 mg, 0.06 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 40 (16 mg, 67%). ¹H NMR (300 MHz, CD₃OD) δ 8.48 (s, 1 H),8.26 (dd, J=4.71, 1.51 Hz, 1 H), 8.13 (s, 1 H), 7.20 (dd, J=7.91, 1.32Hz, 1 H), 6.96 (dd, J=8.10, 4.71 Hz, 1 H), 4.49 (m, 2 H), 4.01 (s, 3 H),3.56 (m, 2 H), 3.42 (s, 3 H), 2.10 (m, 2 H); MS (ES) m/z: 410 (M+H⁺).

EXAMPLE 253-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-pyrimidin-5-yl-pyrrole-2,5-dione(Compound 41)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added boronic acid derivative (0.2 mmol) at 23° C. undernitrogen. The reaction mixture was refluxed at 90° C. for 18 h. Uponcooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 41a (29 mg, 45%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1 H), 8.83 (s, 2 H), 8.30 (d,J=4.76 Hz, 1 H), 8.15 (s, 1 H), 7.88 (s, 1 H), 7.66 (m, 5 H), 7.36 (m, 5H), 6.86 (dd, J=8.05, 4.57 Hz, 1 H), 6.72 (d, J=8.05 Hz, 1 H), 4.55 (m,2 H), 3.68 (m, 2 H), 2.17 (m, 2 H), 1.10 (s, 9 H); MS (ES) m/z: 588(M+H⁺).

To a solution of 41a (29 mg, 0.05 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 41 (11 mg, 64%). ¹H NMR (300 MHz, Acetone-d₆) δ 9.11 (s, 1H), 8.86 (s, 2 H), 8.29 (m, 2 H), 6.95 (m, 2 H), 4.58 (m, 2 H), 3.55 (m,2 H), 2.11 (m, 2 H); MS (ES) m/z: 348 (M−H⁺).

EXAMPLE 263-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-quinolin-8-yl-pyrrole-2,5-dione(Compound 42)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added boronic acid derivative (0.2 mmol) at 23° C. undernitrogen. The reaction mixture was refluxed at 90° C. for 18 h. Uponcooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 42a (37.5 mg, 59%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.72 (dd, J=4.14, 1.70 Hz, 1 H), 8.16(m, 2 H), 8.07 (dd, J=4.71, 1.51 Hz, 1 H), 7.91 (dd, J=8.29, 1.51 Hz, 1H), 7.83 (s, 1 H), 7.65 (m, 5 H), 7.54 (m, 1 H), 7.36 (m, 7 H), 6.41(dd, J=8.10, 4.71 Hz, 1 H), 6.25 (dd, J=8.10, 1.51 Hz, 1 H), 4.48 (m, 2H), 3.66 (m, 2 H), 2.11 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 637(M+H⁺).

To a solution of 42a (37.5 mg, 0.059 mmol) in THF (1 mL) was added TBAF(1 M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours,the mixture was concentrated and purified by column chromatography(SiO₂) to give Compound 42 (20 mg, 85%) as an orange solid. ¹H NMR (300MHz, Acetone-d₆) δ 8.69 (dd, J=3.96, 1.70 Hz, 1 H), 8.37 (dd, J=8.48,1.70 Hz, 1 H), 8.13 (s, 1 H), 8.08 (m, 2 H), 7.78 (dd, J=6.97, 1.51 Hz,1 H), 7.65 (dd, J=8.10, 7.35 Hz, 1 H), 7.45 (dd, J=8.48, 4.14 Hz, 1 H),6.52 (m, 2 H), 4.44 (m, 2 H), 3.46 (m, 2 H), 1.99 (m, 2 H); MS (ES) m/z:399 (M+H⁺).

EXAMPLE 273-Benzo[b]thiophen-2-yl-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 43)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added boronic acid derivative (0.2 mmol) at 23° C. undernitrogen. The reaction mixture was refluxed at 90° C. for 18 h. Uponcooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 43a (40 mg, 61%). ¹H NMR (300MHz, CDCl₃) 8.48 (dd, J=8.10, 1.70 Hz, 1 H), 8.40 (d, J=4.71 Hz, 1 H),8.21 (s, 1 H), 7.68 (m, 7 H), 7.38 (m, 9 H), 7.20 (m, 1 H), 4.63 (m, 2H), 3.75 (m, 2 H), 2.18 (m, 2 H), 1.10 (s, 9 H); MS (ES) m/z: 662(M+H⁺).

To a solution of 43a (40 mg, 0.06 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 43 (16 mg, 66%). ¹H NMR (300 MHz, Acetone-d₆) δ 8.52 (dd,J=8.10, 1.51 Hz, 1H), 8.39 (m, 2 H), 8.32 (dd, J=4.71, 1.51 Hz, 1H),8.18 (s, 1 H), 7.83 (m, 1 H), 7.39 (m, 2 H), 7.27 (dd, J=8.10, 4.71 Hz,1 H), 6.97 (dd, J=8.10, 4.71 Hz, 1 H), 4.59 (m, 2 H), 3.58 (m, 2 H),2.14 (m, 2 H); MS (ES) m/z: 404 (M+H⁺).

EXAMPLE 283-(3,5-Dimethyl-isoxazol-4-yl)-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 44)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol), Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) in THF(1 mL) was added boronic acid derivative (0.2 mmol) at 23° C. undernitrogen. The reaction mixture was refluxed at 90° C. for 18 h. Uponcooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 44a (9 mg, 15%). ¹H NMR (300 MHz,CDCl₃), 8.32 (d, J=3.11 Hz, 1 H), 8.21 (s, 1 H), 7.64 (m, 4 H), 7.58 (s,1 H), 7.35 (m, 6 H), 6.99 (m, 2 H), 4.59 (m, 2 H), 3.64 (m, 2 H), 2.16(m, 2 H), 1.09 (s, 9 H); MS (ES) m/z: 605 (M+H⁺).

To a solution of 44a (9 mg, 0.015 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 44 (3.5 mg, 64%). ¹H NMR (300 MHz, Acetone-d₆) δ 8.33 (dd,J=4.57, 1.46 Hz, 1 H), 8.24 (s, 1 H), 7.24 (dd, J=8.05, 1.65 Hz, 1 H),7.03 (dd, J=8.05, 4.76 Hz, 1 H), 4.56 (m, 2 H), 3.53 (m, 2 H), 2.11 (m,2 H), 2.08 (s, 3 H), 2.02 (s, 3 H); MS (ES) m/z: 365 (M−H⁺).

EXAMPLE 293-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(2-oxo-2H-pyran-3-yl)-pyrrole-2,5-dione(Compound 45)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 45a (30 mg, 50%). ¹H NMR (300MHz, CDCl₃) 8.32 (d, J=4.71 Hz, 1 H), 8.17 (s, 1 H), 7.96 (s, 1 H), 7.67(m, 5 H), 7.65 (dd, J=5.09, 2.07 Hz, 1 H), 7.37 (m, 7 H), 6.99 (dd,J=7.91, 4.71 Hz, 1 H), 6.39 (m, 1 H), 4.52 (m, 2 H), 3.44 (m, 2 H), 2.06(m, 2 H), 1.05 (s, 9 H); MS (ES) m/z: 604 (M+H⁺).

To a solution of 45a (38 mg, 0.063 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 45 (3 mg, 13%) as an orange solid. ¹H NMR (300 MHz,Acetone-d₆) δ 8.30 (dd, J=4.71, 1.51 Hz, 1 H), 8.11 (s, 1 H), 7.80 (dd,J=6.78, 2.26 Hz, 1 H), 7.61 (dd, J=5.09, 2.07 Hz, 1 H), 7.50 (dd,J=7.91, 1.32 Hz, 1 H), 7.02 (dd, J=7.91, 4.71 Hz, 1 H), 6.46 (dd,J=6.78, 5.09 Hz, 1 H), 4.52 (m, 2 H), 3.44 (m, 2 H), 2.06 (m, 2 H); MS(ES) m/z: 366 (M+H⁺).

EXAMPLE 304-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1′-methyl-1′H-[3,3′]bipyrrolyl-2,5-dione(Compound 46)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 46a (35 mg, 60%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.34 (dd, J=4.71, 1.51 Hz, 1 H), 7.74(s, 1 H), 7.64 (m, 4 H), 7.35 (m, 9 H), 6.97 (dd, J=7.91, 4.71 Hz, 1 H),6.43 (m, 1 H), 6.12 (m, 1 H), 4.53 (m, 2 H), 4.01 (m, 1 H), 3.72 (m, 2H), 3.66 (s, 3 H), 2.18 (m, 2 H), 1.09 (s, 9 H); MS (ES) m/z: 589(M+H⁺).

To a solution of 46a (35 mg, 0.06 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 46 (15 mg, 71%) as an orange solid. ¹H NMR (300 MHz,Acetone-d₆) δ 9.54 (s, 1 H), 8.30 (dd, J=4.71, 1.51 Hz, 1 H), 7.89 (s, 1H), 7.50 (dd, J=8.10, 1.70 Hz, 1 H), 7.44 (m, 1 H), 7.02 (dd, J=7.91,4.71 Hz, 1 H), 6.60 (m, 1 H), 6.11 (dd, J=2.83, 1.70 Hz, 1 H), 4.54 (m,2 H), 4.01 (m, 1 H), 3.70 (s, 3 H), 3.55 (m, 2 H), 2.11 (m, 2 H); MS(ES) m/z: 351 (M+H⁺).

EXAMPLE 314-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1′-methyl-1′H-[3,3′]bipyrrolyl-2,5-dione(Compound 47)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 47a (47 mg, 72%). ¹H NMR (300MHz, Acetone-d₆) δ 8.95 (s, 1 H), 8.54 (s, 2 H), 8.34 (s, 1 H), 8.28(dd, J=4.52, 1.32 Hz, 1 H), 7.76 (s, 1 H), 7.64 (m, 6 H), 7.38 (m, 4 H),6.82 (dd, J=8.10, 4.71 Hz, 1 H), 6.66 (dd, J=8.10, 1.51 Hz, 1 H), 4.54(m, 2 H), 3.75 (m, 2 H), 2.16 (m, 2 H), 1.09 (s, 9 H); MS (ES) m/z: 588(M+H⁺).

To a solution of 47a (47 mg, 0.08 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 47 (18 mg, 64%). ¹H NMR (300 MHz, Acetone-d₆) δ 9.01 (s, 1H), 8.58 (m, 1 H), 8.42 (s, 1 H), 8.27 (dd, J=4.39, 1.83 Hz, 1 H), 6.94(m, 2 H), 4.54 (m, 2 H), 3.57 (m, 2 H), 2.11 (m, 2 H); MS (ES) m/z: 351(M+H⁺).

EXAMPLE 321′-Benzyl-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1′H-[3,3′]bipyrrolyl-2,5-dione(Compound 48)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 48a (40 mg, 60%). ¹H NMR (300MHz, CDCl₃) δ 8.29 (d, J=4.57 Hz, 1 H), 7.75 (s, 1 H), 7.65 (m, 4 H),7.37 (m, 12 H), 7.11 (d, J=6.40 Hz, 2 H), 6.89 (dd, J=7.87, 4.57 Hz, 1H), 6.53 (m, 1 H), 6.27 (m, 1 H), 5.00 (s, 2 H), 4.56 (m, 2 H), 3.72 (m,2 H), 2.17 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 665 (M+H⁺).

To a solution of 48a (40 mg, 0.06 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 48 (16 mg, 64%). ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=4.76Hz, 1 H), 7.76 (s, 1 H), 7.59 (s, 1 H), 7.42 (m, 2 H), 7.32 (m, 3 H),7.12 (d, J=6.59 Hz, 2 H), 6.94 (dd, J=7.87, 4.76 Hz, 1 H), 6.55 (m, 1H), 6.25 (m, 1 H), 5.02 (s, 2 H), 4.51 (m, 2 H), 3.46 (m, 2 H), 2.05 (m,2 H); MS (ES) m/z: 427 (M+H⁺).

EXAMPLE 333-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(2-phenyl-oxazol-5-yl)-pyrrole-2,5-dione(Compound 49)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (60 mg, 0.11 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 49a (45 mg, 63%). ¹H NMR (300MHz, CDCl₃) δ 8.36 (dd, J=4.52, 1.51 Hz, 1 H), 8.08 (s, 1 H), 8.01 (s, 1H), 7.64 (m, 4 H), 7.53 (m, 2 H), 7.36 (m, 11 H), 6.95 (dd, J=7.91, 4.71Hz, 1 H), 4.64 (m, 2 H), 3.74 (m, 2 H), 2.22 (m, 2 H), 1.06 (s, 9 H); MS(ES) m/z: 653 (M+H⁺).

To a solution of 49a (45 mg, 0.069 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 49 (21 mg, 74%). ¹H NMR (300 MHz, Acetone-d₆) δ 8.37 (dd,J=4.76, 1.46 Hz, 1 H), 8.27 (s, 1 H), 7.98 (s, 1 H), 7.76 (dd, J=7.87,1.46 Hz, 1 H), 7.48 (m, 3 H), 7.37 (m, 2 H), 7.08 (dd, J=7.87, 4.57 Hz,1 H), 4.65 (m, 2 H), 3.60 (m, 2 H), 2.16 (m, 2 H); MS (ES) m/z: 415(M+H⁺).

EXAMPLE 343-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 50)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (60 mg, 0.11 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 50a (63 mg, 93%). ¹H NMR (300MHz, CDCl₃) δ 8.30 (m, 2 H), 7.92 (s, 1 H), 7.66 (m, 4 H), 7.37 (m, 6H), 7.22 (dd, J=7.54, 6.03 Hz, 1 H), 6.92 (dd, J=7.91, 4.71 Hz, 1 H),6.43 (s, 1 H), 4.54 (m, 2 H), 4.02 (m, 2 H), 3.78 (m, 2 H), 2.90 (m, 2H), 2.17 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 616 (M+H⁺).

To a solution of 50a (63 mg, 0.10 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 50 (36 mg, 93%). ¹H NMR (300 MHz, Acetone-d₆) δ 8.29 (m, 2H), 7.76 (s, 1 H), 7.24 (d, J=8.48 Hz, 1 H), 6.96 (dd, J=7.91, 4.71 Hz,1 H), 6.51 (s, 1 H), 4.50 (m, 2 H), 4.04 (m, 2 H), 3.51 (m, 2 H), 2.95(m, 2 H), 2.61 (m, 2 H), 2.06 (m, 2 H); MS (ES) m/z: 378 (M+H⁺).

EXAMPLE 353-(5,6-Dihydro-[1,4]dioxin-2-yl)-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 51)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (59 mg, 0.11 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 51a (41 mg, 63%). ¹H NMR (300MHz, CDCl₃) δ 8.34 (dd, J=4.57, 1.46 Hz, 1 H), 7.89 (dd, J=7.87, 1.46Hz, 1 H), 7.77 (s, 1 H), 7.66 (m, 4 H), 7.38 (m, 8 H), 7.13 (dd, J=8.05,4.76 Hz, 1 H), 4.51 (m, 2 H), 4.12 (m, 2 H), 3.88 (m, 2 H), 3.74 (m, 2H), 2.14 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 594 (M+H⁺).

To a solution of 51a (41 mg, 0.069 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 51 (19 mg, 77%). ¹H NMR (300 MHz, CDCl₃) δ 8.32 (dd,J=4.71, 1.32 Hz, 1 H), 7.93 (dd, J=7.91, 1.32 Hz, 1 H), 7.76 (s, 1 H),7.39 (s, 1 H), 7.16 (dd, J=7.91, 4.90 Hz, 1 H), 4.49 (m, 2 H), 4.14 (m,2 H), 3.89 (m, 2 H), 3.46 (m, 2 H), 2.05 (m, 2 H); MS (ES) m/z: 356(M+H⁺).

EXAMPLE 363-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-methyl-1H-pyrazol-4-yl)-pyrrole-2,5-dione(Compound 52)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 52a (18 mg, 31%). ¹H NMR (300MHz, CDCl₃) δ 8.32 (s, 1 H), 8.29 (m, 1 H), 7.8 (s, 1 H), 7.65 (m, 5 H),7.39 (m, 8 H), 6.89 (dd, J=8.1, 4.7 Hz, 1 H), 6.49 (m, 2 H), 4.54 (m, 2H), 3.67 (m, 2 H), 3.46 (s, 3 H), 2.16 (m, 2 H), 1.11 (s, 9 H); MS (ES)m/z: 590 (M+H⁺).

To a solution of 52a (18 mg, 0.314 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 52 (11 mg, 100%). ¹H NMR (300 MHz, Acetone-d₆) δ 8.38 (s,1 H), 8.29 (m, 1 H), 8.07 (s, 1 H), 7.51 (s, 1 H), 6.9 (dd, J=8.1, 4.7Hz, 1 H), 6.67 (d, J=2.3 Hz, 1 H), 6.42 (s, 1 H), 4.56 (m, 2 H), 3.51(m, 5 H), 2.05 (m, 2 H); MS (ES) m/z: 352 (M+H⁺).

EXAMPLE 373-Furan-2-yl-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 53)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 53a (42 mg, 73%). ¹H NMR (300MHz, CDCl₃) δ 8.33 (dd, J=4.71, 1.51 Hz, 1 H), 7.92 (s, 1 H), 7.76 (s, 1H), 7.64 (m, 4 H), 7.48 (dd, J=7.91, 1.32 Hz, 1 H), 7.35 (m, 7 H), 7.26(m, 1 H), 6.99 (dd, J=8.10, 4.71 Hz, 1 H), 6.55 (dd, J=3.58, 1.88 Hz, 1H), 4.58 (m, 2 H), 3.77 (m, 2 H), 2.18 (m, 2 H), 1.07 (s, 9 H); MS (ES)m/z: 576 (M+H⁺).

To a solution of 53a (41 mg, 0.07 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 53 (21 mg, 87%). ¹H NMR (300 MHz, CDCl₃) δ 8.31 (dd,J=4.71, 1.32 Hz, 1 H), 7.96 (s, 1 H), 7.57 (s, 1 H), 7.51 (dd, J=8.10,1.51 Hz, 1 H), 7.39 (d, J=1.13 Hz, 1 H), 7.31 (d, J=3.58 Hz, 1 H), 7.03(dd, J=8.10, 4.71 Hz, 1 H), 6.58 (dd, J=3.58, 1.70 Hz, 1 H), 4.54 (m, 2H), 3.50 (m, 2 H), 2.07 (m, 2 H); MS (ES) m/z: 338 (M+H⁺).

EXAMPLE 383-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)-pyrrole-2,5-dione(compound 54)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (60 mg, 0.11 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 54a (53 mg, 76%). ¹H NMR (300MHz, CDCl₃) δ 8.39 (s, 1 H), 8.30 (dd, J=4.71, 1.51 Hz, 1 H), 7.90 (s, 1H), 7.66 (m, 4 H), 7.37 (m, 6 H), 7.19 (dd, J=8.10, 1.51 Hz, 1 H), 6.93(dd, J=7.91, 4.71 Hz, 1 H), 6.46 (s, 1 H), 4.53 (m, 2 H), 4.00 (m, 2 H),3.76 (m, 2 H), 2.82 (m, 2 H), 2.17 (m, 2 H), 1.99 (m, 2 H), 1.85 (m, 2H), 1.07 (s, 9 H); MS (ES) m/z: 630 (M+H⁺).

To a solution of 54a (53 mg, 0.084 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 54 (31 mg, 94%). ¹H NMR (300 MHz, CDCl₃) δ 8.33 (s, 1 H),8.27 (dd, J=4.71, 1.32 Hz, 1 H), 7.53 (s, 1 H), 7.19 (dd, J=8.10, 1.51Hz, 1 H), 6.98 (dd, J=8.10, 4.71 Hz, 1 H), 6.51 (s, 1 H), 4.50 (m, 2 H),4.00 (m, 2 H), 3.48 (m, 2 H), 2.85 (m, 2 H), 2.06 (m, 4 H), 1.89 (m, 2H); MS (ES) m/z: 392 (M+H⁺).

EXAMPLE 393-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-thiazol-2-yl-pyrrole-2,5-dione(Compound 55)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (54 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 55a (6.5 mg, 11%). ¹H NMR (300MHz, CDCl₃) δ 8.69 (s, 1 H), 8.34 (dd, J=4.71, 1.51 Hz, 1 H), 7.87 (d,J=2.3 Hz, 1 H), 7.64 (m, 4 H), 7.36 (m, 9 H), 7.03 (dd, J=7.91, 4.71 Hz,1 H), 4.57 (m, 2 H), 3.73 (m, 2 H), 2.18 (m, 2 H), 1.08 (s, 9 H); MS(ES) m/z: 593 (M+H⁺).

To a solution of 55a (5.4 mg, 0.009 mmol) in THF (1 mL) was added TBAF(1 M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours,the mixture was concentrated and purified by column chromatography(SiO₂) to give Compound 55 (2.6 mg, 80%). ¹H NMR (300 MHz, Acetone-d₆) δ8.89 (s, 1 H), 8.33 (d, J=2.1 Hz, 1 H), 7.94 (m, 2 H), 7.71 (d, J=2.3Hz, 1 H), 7.1 (dd, J=8.1, 4.7 Hz, 1 H), 4.58 (m, 2 H), 3.99 (m, 1 H),3.61 (m, 2 H), 2.14 (m, 2 H); MS (ES) m/z: 355 (M+H⁺).

EXAMPLE 403-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-pyrimidin-2-yl-pyrrole-2,5-dione(Compound 56)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (60 mg, 0.1 mmol) and Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) inTHF (1 mL) was added stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 56a (45 mg, 70%). ¹H NMR (300MHz, CDCl₃) δ 8.83 (m, 2 H), 8.33 (s, 1 H), 8.26 (dd, J=4.52, 1.13 Hz, 1H), 8.16 (s, 1 H), 7.66 (m, 4 H), 7.38 (m, 6 H), 7.25 (m, 1 H), 6.78(dd, J=4.71, 3.39 Hz, 1 H), 6.53 (dd, J=8.10, 1.32 Hz, 1 H), 4.52 (m, 2H), 3.77 (m, 2 H), 2.16 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 588(M+H⁺).

To a solution of 56a (45 mg, 0.077 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 56 (28 mg, 100%). ¹H NMR (300 MHz, CD₃OD) δ 8.85 (d,J=4.94 Hz, 2 H), 8.32 (s, 1 H), 8.21 (d, J=4.03 Hz, 1 H), 7.49 (m, 1 H),6.87 (dd, J=8.05, 4.76 Hz, 1 H), 6.68 (d, J=7.87 Hz, 1 H), 4.47 (m, 2H), 3.56 (m, 2 H), 2.08 (m, 2 H); MS (ES) m/z: 349 (M−H⁺).

EXAMPLE 413-(2,4-Dimethoxy-pyrimidin-5-yl)-4-[1-(3-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 57)

To a solution of the amide 15a (0.5 g, 2.7 mmol) in DMF (10 mL) wasadded Cs₂CO₃ (3 eq) and 3-phenyl-propyl bromide (1.5 eq). The reactionwas heated at 70° C. for 2 hours. After cooling down, the solution wasdiluted with EtOAc and washed with H₂O. The organic layer was dried(MgSO₄), concentrated and chromatographed on silica to give 57a (0.412g, 49%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.36 (dd, J=4.71,1.51 Hz, 1 H), 7.88 (dd, J=7.91, 1.51 Hz, 1 H), 7.22 (m, 6 H), 7.10 (m,1 H), 4.32 (m, 2 H), 3.70 (s, 2 H), 2.66 (m, 2 H); MS (ES) m/z: 316(M+H⁺).

To a solution of 57a (0.412 g, 1.3 mmol) in DMF (10 mL) at 0° C. wasadded (CO₂Et)₂ (2 eq), and then ^(t)BuOK (2 eq, 1 M in THF) was addeddropwise. The resulting red solution was stirred for 15 minutes thenconcentrated and chromatographed on silica. The product 57b (0.393 g,81%) was obtained as a yellow solid. ¹H NMR (300 MHz, Acetone-d₆) δ 9.11(s, 1 H), 8.75 (m, 1 H), 8.10 (m, 1 H), 7.97 (s, 1 H), 7.12 (m, 5 H),6.88 (m, 1 H), 4.15 (m, 2 H), 2.45 (m, 2 H), 2.04 (m, 2 H); MS (ES) m/z:374 (M−H⁺).

To a solution of 57b (0.393 g, 1.05 mmol) in DMF and CH₂Cl₂ (1:1) wasadded (COCl)₂ (3 eq) in one portion at 0° C. The reaction was followedby TLC until starting material disappeared (˜1 hour), then NaHCO₃solution was added. The mixture was diluted with EtOAc and washed withwater, dried, concentrated and chromatographed on silica giving theproduct 57c (0.372 g, 89%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ8.46 (dd, J=8.10, 1.51 Hz, 1 H), 8.43 (dd, J=4.71, 1.51 Hz, 1 H), 7.75(s, 1 H), 7.24 (m, 7 H), 4.41 (m, 2 H), 2.70(m, 2 H), 2.30 (m, 2 H); MS(ES) m/z: 366 (M+H⁺).

To a solution of 57c (30 mg, 0.082 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 57 (6 mg, 16%). ¹H NMR (300 MHz,CDCl₃) δ 8.50 (s, 1 H), 8.31 (dd, J=4.71, 1.51 Hz, 1 H), 8.09 (s, 1 H),7.59 (s, 1 H), 7.31 (m, 2 H), 7.20 (m, 4 H), 7.05 (dd, J=7.91, 1.32 Hz,1 H), 6.90 (dd, J=7.91, 4.71 Hz, 1 H), 4.41 (m, 2 H), 4.04 (s, 3 H),3.43 (s, 3 H), 2.69 (m, 2 H), 2.29 (m, 2 H); MS (ES) m/z: 470 (M+H⁺).

EXAMPLE 423-[1-(3-Phenyl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-pyrimidin-5-yl-pyrrole-2,5-dione(Compound 58)

To a solution of 57c (30 mg, 0.083 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (1 mL) was added boronic acid derivative (2 eq) and KF (3 eq) at 23°C. under nitrogen. The reaction mixture was refluxed at 90° C. for 18 h.Upon cooling, the mixture was diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 58 (13 mg, 36%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 1 H), 8.89 (s, 2 H), 8.33 (dd,J=4.71, 1.51 Hz, 1 H), 8.16 (s, 1 H), 7.23 (m, 6 H), 6.90 (dd, J=7.91,4.71 Hz, 1 H), 6.74 (dd, J=8.10, 1.32 Hz, 1 H), 4.42 (m, 2 H), 2.73 (m,2 H), 2.35 (m, 2 H); MS (ES) m/z: 437 (M+H⁺).

EXAMPLE 433-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-4-[1-(3-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 59)

To a solution of 57c (30 mg, 0.082 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 59 (32 mg, 89%). ¹H NMR (300 MHz,CDCl₃) δ 8.32 (m, 2 H), 7.50 (s, 1 H), 7.24 (m, 6 H), 6.95 (dd, J=8.10,4.71 Hz, 1 H), 6.45 (s, 1 H), 4.38 (m, 2 H), 4.03 (m, 2 H), 2.93 (m, 2H), 2.74 (m, 2 H), 2.59 (m, 2 H), 2.30 (m, 2 H); MS (ES) m/z: 438(M+H⁺).

EXAMPLE 443-[1-(3-Phenyl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-pyrazin-2-yl-pyrrole-2,5-dione(Compound 60)

To a solution of 57c (30 mg, 0.083 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (1 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 60 (20 mg, 59%). ¹H NMR (300 MHz,CDCl₃) δ 9.01 (d, J=1.32 Hz, 1 H), 8.55 (m, 2 H), 8.30 (m, 2 H), 7.73(s, 1 H), 7.26 (m, 5 H), 6.85 (dd, J=7.91, 4.71 Hz, 1 H), 6.64 (dd,J=7.91, 1.51 Hz, 1 H), 4.39 (m, 2 H), 2.74 (m, 2 H), 2.31 (m, 2 H); MS(ES) m/z: 410 (M+H⁺).

EXAMPLE 453-(5,6-Dihydro-4H-pyran-2-yl)-4-[1-(3-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 61)

To a solution of 57c (30 mg, 0.083 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (1 mL) was added the stannane derivative (1.5 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 61 (29 mg, 85%). ¹H NMR (300 MHz,CDCl₃) δ 8.39 (dd, J=4.71, 1.32 Hz, 1 H), 8.18 (s, 1 H), 7.97 (dd,J=7.91, 1.32 Hz, 1 H), 7.92 (s, 1 H), 7.22 (m, 6 H), 5.82 (m, 1 H), 4.38(m, 2 H), 3.83 (m, 2 H), 2.71 (m, 2 H), 2.29 (m, 4 H), 1.85 (m, 2 H); MS(ES) m/z: 414 (M+H⁺).

EXAMPLE 464-{3-[4-(2,4-Dimethoxy-pyrimidin-5-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrrolo[2,3-b]pyridin-1-yl}-butyronitrile(Compound 62)

To a solution of the amide 15a (0.25 g, 1.43 mmol) in DMF (5 mL) wasadded Cs₂CO₃ (3 eq) and 3-cyano-propyl bromide (1.5 eq). The reactionwas heated at 80° C. for 2 hours. After cooling down, the solution wasfiltered through celite and then concentrated and chromatographed onsilica to give 62a (0.146 g, 42%). ¹H NMR (300 MHz, CDCl₃) δ 8.33 (dd,J=4.71, 1.51 Hz, 1 H), 7.91 (dd, J=7.91, 1.51 Hz, 1 H), 7.20 (s, 1 H),7.13 (dd,J=7.91, 4.71 Hz, 1 H), 4.47 (m, 2 H), 3.71 (s, 2 H), 2.38 (m, 2H), 2.29 (m, 2 H); MS (ES) m/z: 243 (M+H⁺).

To a solution of 62a (0.146 g, 0.6 mmol) in THF (10 mL) at 0° C. wasadded (CO₂Et)₂ (2 eq), and then ^(t)BuOK (2 eq, 1 M in THF) was addeddropwise. After stirring for 1 hour, the solution was concentrated andchromatographed on silica gel. The product 62b (0.131 g, 73%) wasobtained as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 8.65 (dd, J=8.05,1.65 Hz, 1 H), 8.17 (dd, J=4.76, 1.46 Hz, 1 H), 7.69 (s, 1 H), 7.06 (dd,J=7.87, 4.76 Hz, 1 H), 4.38 (m, 2 H), 2.43 (m, 2 H), 2.21 (m, 2 H); MS(ES) m/z: 297 (M+H⁺).

To a solution of 62b (0.131 g, 0.44 mmol) in DMF and CH₂Cl₂ (1:1) wasadded (COCl)₂ (3 eq) dropwise at room temperature. The reaction wasfollowed by TLC until the starting material disappeared. NaHCO₃ solutionwas added and the aqueous layer was discarded. The organic layer waswashed with water, dried, concentrated and chromatographed on silicagiving the product 62c (0.107 g, 77%) as an orange solid. ¹H NMR (300MHz, CD₃OD) δ 8.52 (dd, J=8.10, 1.51 Hz, 1 H), 8.39 (dd, J=4.71, 1.51Hz, 1 H), 8.32 (s, 1 H), 7.26 (dd, J=8.10, 4.71 Hz, 1 H), 4.53 (m, 2 H),2.51 (m, 2 H), 2.28 (m, 2 H); MS (ES) m/z: 315 (M+H⁺).

To a solution of 62c (30 mg, 0.095 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 62 (17 mg, 43%). ¹H NMR (300 MHz,CDCl₃) δ 8.46 (s, 1 H), 8.29 (dd, J=4.71, 1.51 Hz, 1 H), 8.07 (s, 1 H),7.07 (dd, J=7.91, 1.51 Hz, 1 H), 6.92 (dd, J=7.91, 4.71 Hz, 1 H), 4.50(s, 2 H), 4.04 (s, 3 H), 3.48 (s, 3 H) 2.36 (m, 4 H); MS (ES) m/z: 419(M+H⁺).

EXAMPLE 474-[3-(2,5-Dioxo-4-pyrazin-2-yl-2,5-dihydro-1H-pyrrol-3-yl)-pyrrolo[2,3-b]pyridin-1-yl]-butyronitrile(Compound 63)

To a solution of 62c (30 mg, 0.094 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 63 (23 mg, 68%). ¹H NMR (300 MHz,CDCl₃) δ 9.04 (s, 1 H), 8.57 (s, 2 H), 8.30 (m, 2 H), 7.82 (s, 1 H),6.89 (dd, J=7.87, 4.39 Hz, 1 H), 6.75 (d, J=7.87 Hz, 1 H), 4.52 (m, 2H), 2.44 (m, 2 H), 2.37 (m, 2 H); MS (ES) m/z: 357 (M−H⁺).

EXAMPLE 484-{3-[4-(1-Methyl-1H-pyrazol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrrolo[2,3-b]pyridin-1-yl}-butyronitrile(Compound 64)

To a solution of 62c (60 mg, 0.19 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 64 (23 mg, 33%). ¹H NMR (300 MHz,CDCl₃) δ 8.31 (m, 2 H), 7.45 (m, 2 H), 7.22 (dd, J=8.05, 1.46 Hz, 1 H),6.99 (dd, J=8.05, 4.76 Hz, 1 H), 6.80 (d, J=2.38 Hz, 1 H), 4.51 (s, 2H), 3.85 (s, 3 H), 2.44 (m, 2 H), 2.36 (s, 2 H); MS (ES) m/z: 361(M+H⁺).

EXAMPLE 493-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-4-[1-(3-phenoxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 65)

To a solution of the amide 15a (0.25 g, 1.44 mmol) in DMF (5 mL) wasadded Cs₂CO₃ (3 eq) and 3-phenoxyl-propyl bromide (1.5 eq). The reactionwas heated at 80° C. for 2 hours. After cooling down, the solution wasfiltered through celite and then concentrated and chromatographed onsilica to give 65a (0.12 g, 27%). ¹H NMR (300 MHz, CDCl₃) δ 8.33 (dd,J=4.57, 1.28 Hz, 1 H), 7.89 (dd, J=7.87, 1.28 Hz, 1 H), 7.26 (m, 2 H),7.16 (s, 1 H), 7.08 (dd, J=7.87, 4.57 Hz, 1 H), 6.94 (m, 1 H), 6.86 (m,2 H), 4.49 (m, 2 H), 3.92 (m, 2 H), 3.64 (s, 2 H), 2.36 (m, 2 H); MS(ES) m/z: 310 (M+H⁺).

To a solution of 65a (0.12 g, 0.39 mmol) in THF (10 mL) at ⁰° C. wasadded (CO₂Et)₂ (2 eq), and then ^(t)BuOK (2 eq, 1 M in THF) was addeddropwise. After stirring for 1 hour, the solution was concentrated andchromatographed on silica gel. The product 65b (74 mg, 53%) was obtainedas a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.50 (m, 1 H), 8.41 (m, 1H), 8.17 (s, 1 H), 7.25 (m, 4 H), 7.21 (m, 1 H), 6.86 (m, 2 H), 4.62 (m,2 H), 3.98 (m, 2 H), 2.44 (m, 2 H); MS (ES) m/z: 364 (M+H⁺).

To a solution of 65b (74 mg, 0.2 mmol) in DMF and CH₂Cl₂ (1:1) was added(COCl)₂ (3 eq) dropwise at room temperature. The reaction was followedby TLC until the starting material disappeared. NaHCO₃ solution wasadded and the aqueous layer was discarded. The organic layer was washedwith water, dried, concentrated and chromatographed on silica giving theproduct 65c (61 mg, 78%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ8.39 (dd, J=4.90, 1.51 Hz, 1 H), 7.97 (dd, J=7.91, 1.51 Hz, 1 H), 7.25(m, 4 H), 7.14 (dd, J=7.91, 4.90 Hz, 1 H), 6.95 (m, 1 H), 6.86 (m, 2 H),4.53 (m, 2 H), 3.95 (m, 2 H), 2.35 (m, 2 H); MS (ES) m/z: 382 (M+H⁺).

To a solution of 65c (30 mg, 0.079 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 65 (12 mg, 34%). ¹H NMR (300 MHz,CDCl₃) δ 8.32 (m, 2 H), 7.49 (s, 1 H), 7.26 (m, 3 H), 6.94 (m, 4 H),6.46 (s, 1 H), 4.59 (m, 2 H), 4.05 (m, 4 H), 2.92 (m, 2 H), 2.59 (m, 2H), 2.43 (m, 2 H); MS (ES) m/z: 454 (M+H⁺).

EXAMPLE 503-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(2-methyl-2H-pyrazol-3-yl)-pyrrole-2,5-dione(Compound 66)

Cesium carbonate (3.5 g, 10.8 mmol) and iodomethane (0.51 g, 3.6 mmol)were added to a solution of 2-(1H-pyrazol-3-yl)-acetamide Compound 9a(0.45 g, 3.6 mmol) in DMF (5 mL) at 23° C. under nitrogen. The mixturewas warmed to 70° C. and stirred for 3 hours. After cooling, the mixturewas diluted with EtOAc (20 mL), filtered through celite and washed withwater (4×10 mL). The organic layer was dried (MgSO₄), filtered andconcentrated to give a first crude product (0.46 g) as a white solid. Bychromatography, the first crude product was shown to be a 2:1 mixture of2-(1-methyl-1H-pyrazol-3-yl)-acetamide and2-(2-methyl-2H-pyrazol-3-yl)-acetamide.

Potassium tert-butoxide (6.6 mL, 6.6 mmol; 1 M solution in THF) wasadded dropwise to a solution of the first crude product and Compound 1c(1.36 g, 3.47 mmol) in THF (20 mL) at 0° C. under nitrogen. Afterwarming to 23° C., the reaction was stirred for 2 h then concentratedand purified by column chromatography (SiO₂) to give a second crudeproduct (0.46 g) as a yellow solid which was then recrystallized(EtOAc/Hexanes) to give Compound 66a, ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s,1 H), 8.30 (s, 1 H), 8.25 (dd, J=4.76, 1.46 Hz, 1 H), 7.56 (d, J=2.01Hz, 1 H), 6.83 (dd, J=8.05, 4.57 Hz, 1 H), 6.47 (dd, J=8.05, 1.46 Hz, 1H), 6.45 (d, J=1.83 Hz, 1 H), 4.43 (m, 2 H), 3.61 (m, 2 H), 3.47 (s, 3H), 2.07 (m, 2 H), 0.87 (s, 9 H), 0.00 (s, 6 H); MS (ES) m/z: 466(M+H⁺).

TBAF (1.3 mL, 1 M solution in THF, 1.3 mmol) was added to a solution of66a (92 mg, 0.20 mmol) in THF (15 mL) at 23° C. dropwise under nitrogen.After 18 hours, the mixture was concentrated and the crude product wasthen recrystallized (CH₂Cl₂:Hexane) to give Compound 66 (64 mg, 91%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.28 (m, 2 H), 7.62 (d, J=1.88Hz, 1 H), 6.94 (dd, J=8.48, 5.09 Hz, 1 H), 6.59 (dd, J=8.10, 1.32 Hz, 1H), 6.51 (d, J=1.70 Hz, 1 H), 4.53 (m, 2 H), 4.13 (m, 1 H), 3.54 (s, 3H), 3.43 (m, 2 H), 2.07 (m, 2 H); MS (ES) m/z: 352 (M+H⁺).

EXAMPLE 513-Furan-3-yl-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 67)

The boronic acid derivative (0.032 mL, 0.2 mmol) was added to a solutionof3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.054 g, 0.1 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Pd(^(t)Bu₃P)₂ (5 mg, 0.01 mmol) and potassium fluoride (20 mg, 0.34mmol) in THF (1 mL) at 23° C. under nitrogen. The reaction mixture wasstirred at 23° C. for 18 h, diluted with EtOAc (10 mL), then filteredthrough Celite and concentrated. The product was purified by columnchromatography (SiO₂) to give Compound 67a (40 mg, 68%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J=3.20, 1.32 Hz, 1 H), 8.11(s, 1 H), 8.05 (s, 1 H), 7.85 (s, H), 7.63 (m, 4 H), 7.36 (m, 8 H), 7.02(dd, J=7.91, 4.71 Hz, 1 H), 6.32 (d, J=1.32 Hz, 1 H), 4.57 (m, 2 H),3.72 (m, 2 H), 2.19 (m, 2 H), 1.08 (s, 9 H); MS (ES) m/z: 576 (M+H⁺).

To a solution of 67a (39 mg, 0.064 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 67 (20 mg, 87%) as an orange solid. ¹H NMR (300 MHz,Acetone-d₆) δ 8.34 (d, J=4.52, 1.51 Hz, 1 H), 8.16 (m, 1 H), 8.01 (s, 1H), 7.53 (m, H), 7.11 (dd, J=8.10, 4.71 Hz, 1 H), 6.47 (dd, J=2.07, 0.75Hz, 1 H), 4.56 (m, 2 H), 3.59 (m, 2 H), 2.13 (m, 2 H); MS (ES) m/z: 338(M+H⁺).

EXAMPLE 525-{4-[1-(3-Hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl}-1H-pyrimidine-2,4-dione(Compound 68)

To a solution of 40 (14 mg, 0.034 mmol) in MeOH (1 mL) at roomtemperature was added HCl (2 M in Et₂O, 2 eq) and the mixture wasstirred at 60° C. for 180 minutes. After concentration and vacuumdrying, 68 was obtained as a yellow solid (10 mg, 77%); ¹H NMR (300 MHz,DMSO-d₆) δ 11.40 (d, J=5.65 Hz, 1 H), 11.13 (s, 1 H), 11.06 (s, 1 H),8.29 (d, J=3.96 Hz, 1 H), 8.09 (s, 1 H), 7.74 (dd, J=11.87, 8.29 Hz, 2H), 7.13 (dd, J=7.91, 4.71 Hz, 1 H), 4.40 (m, 2 H), 3.39 (m, 2 H), 1.95(m, 2 H); MS (ES) m/z: 382 (M+H⁺).

EXAMPLE 533-{3-[4-(1-Methyl-1H-pyrazol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrrolo[2,3-b]pyridin-1-yl}-propionitrile(Compound 69)

To a solution of the amide 15a (125 mg, 0.58 mmol) in DMF (5 mL) wasadded Cs₂CO₃ (3 eq) and 2-cyano-ethyl bromide (1.5 eq). The reaction washeated at 80° C. for 2 hours. After cooling down, the solution wasfiltered through celite and then concentrated and the crude product wascarried through to the next step.

To a solution of the above crude intermediate in THF (10 mL) at 0° C.was added (CO₂Et)₂ (2 eq), and then ^(t)BuOK (2 eq, 1 M in THF) wasadded dropwise. After stirring for 1 hour, the solution was concentratedand the crude product was carried through to the next step.

To a solution of the above intermediate in DMF and CH₂Cl₂ (1:1) wasadded (COCl)₂ (3 eq) dropwise at room temperature. The reaction wasfollowed by TLC until starting material disappeared. NaHCO₃ solution wasadded and the aqueous layer was discarded. The organic layer was washedwith water, dried, concentrated and the crude product was carriedthrough to the next step.

To a solution of the above intermediate and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 69 (20 mg, 10% for the totalyield of 4 steps). ¹H NMR (300 MHz, CD₃OD) δ 8.37 (s, 1 H), 8.28 (dd,J=4.71, 1.51 Hz, 1 H), 7.67 (d, J=2.26 Hz, 1 H), 7.14 (dd, J=7.91, 1.51Hz, 1 H), 7.02 (dd, J=7.91, 4.71 Hz, 1 H), 6.68 (d, J=2.26 Hz, 1 H),4.69 (m, 2 H), 3.81 (s, 3 H), 3.13 (m, 2 H); MS (ES) m/z: 345 (M−H⁺).

EXAMPLE 543-Butyl-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 70)

To a solution of3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dioneCompound 15d (0.96 g, 1.77 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) in THF (1mL) was added boronic acid derivative (2 eq) at 23° C. under nitrogen.The reaction mixture was refluxed at 90° C. for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL), then filtered through Celite andconcentrated. The product was purified by column chromatography (SiO₂)to give Compound 70a (0.3 g, 30%) as a yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 8.38 (dd, J=3.29, 0.91 Hz, 1 H), 8.03 (dd, J=8.05, 1.10 Hz, 1H), 7.65 (m, 1 H), 7.39 (m, 1 H), 7.16 (dd, J=7.87, 4.57 Hz, 1 H), 4.55(m, 2 H), 3.71 (m, 2 H), 2.62 (m, 2 H), 2.14 (s, 2 H), 1.60 (m, 2 H),1.35 (m, 2 H), 1.09 (s, 9 H), 0.88 (t, J=7.32 Hz, 3 H); MS (ES) m/z: 566(M+H⁺).

To a solution of 70a (50 mg, 0.088 mmol) in THF (1 mL) was added TBAF (1M solution in THF, 1.5 eq) dropwise under nitrogen. After 18 hours, themixture was concentrated and purified by column chromatography (SiO₂) togive Compound 70 (20 mg, 69%) as an orange solid. ¹H NMR (300 MHz,CDCl₃) δ 8.35 (d, J=4.57 Hz, 1 H), 8.06 (d, J=8.05, 1 H), 7.65 (s, 1 H),7.21 (dd, J=8.05, 4.76 Hz, 1 H), 4.51 (m, 2 H), 3.47 (m, 2 H), 2.64 (m,2 H), 2.04 (m, 2 H), 1.62 (m, 2 H), 1.37 (m, 2 H), 0.88 (t, J=7.32 Hz, 3H); MS (ES) m/z: 328 (M+H⁺).

EXAMPLE 553-(2,4-Dimethoxy-pyrimidin-5-yl)-4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 71)

To a solution of the amide 15a (0.25 g, 1.42 mmol) in DMF (5 mL) wasadded, Cs₂CO₃ (3 eq) and 2-methoxy-ethyl bromide (1.5 eq). The reactionwas heated at 80° C. for 2 hours. After cooling down, the solution wasfiltered through celite and then concentrated and the crude product wascarried through to the next step.

To a solution of the above crude intermediate in THF (10 mL) at 0° C.was added (CO₂Et)₂ (2 eq), and then ^(t)BuOK (2 eq, 1 M in THF) wasadded dropwise. After stirring for 1 hour, the solution was concentratedand the crude product was carried through to the next step.

To a solution of the above intermediate in DMF and CH₂Cl₂ (1:1) wasadded (COCl)₂ (3 eq) dropwise at room temperature. The reaction wasfollowed by TLC until the starting material disappeared. NaHCO₃ solutionwas added and the aqueous layer was discarded. The organic layer waswashed with water, dried, concentrated and purified by columnchromatography to get compound 71a (0.2 g, total yield 46% for the 3steps). ¹H NMR (300 MHz, CD₃OD) δ 8.49 (dd, J=8.10, 1.51 Hz, 1 H), 8.41(dd, J=4.71, 1.51 Hz, 1 H), 8.29 (s, 1 H), 7.47 (s, 1 H), 7.22 (dd,J=8.10, 4.71 Hz, 1 H), 4.57 (m, 2 H), 3.78 (m, 2 H), 3.36 (s, 3 H); MS(ES) m/z: 306 (M+H⁺).

To a solution of 71a (20 mg, 0.065 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 71 (8 mg, 30%). ¹H NMR (300 MHz,CD₃OD) δ 8.50 (s, 1 H), 8.29 (dd, J=4.57, 0.91 Hz, 1 H), 8.10 (s, 1 H),7.83 (s, 1 H), 7.13 (dd, J=7.87, 1.10 Hz, 1 H), 6.92 (dd, J=8.05, 4.76Hz, 1 H), 4.54 (m, 2 H), 4.05 (s, 3 H), 3.78 (m, 2 H), 3.45 (s, 3 H),3.33 (s, 3 H); MS (ES) m/z: 410 (M+H⁺).

EXAMPLE 563-(1-Benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(2,4-dimethoxy-pyrimidin-5-yl)-pyrrole-2,5-dione(Compound 72)

A solution EtMgBr (26.6 mL, 3 M in Et₂O) was added dropwise under argonto a well-stirred solution of 7-azaindole (9 g, 76 mmol) in dry toluene(270 mL) at room temperature. After 1 h, a solution of thedichloromaleimide (4.5 g, 38 mmol) in toluene (240 mL) was slowly added.After 15 min, anhydrous CH₂Cl₂ (300 mL) was added and the reactionmixture was heated at 50° C. for 24 h. Hydrolysis was performed by asaturated solution of NH₄Cl till pH 7. After extraction with EtOAc(2×400 mL), the combined organic layers were dried over MgSO₄, filteredand the solvent was removed under reduced pressure. Compound 72a wasprecipitated from methanol, filtered, washed with methanol and driedunder vacuum. Compound 72a was obtained as an orange solid (2.12 g,21%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.71 (s, 1 H), 8.34 (m, 2 H), 8.21(s, 2 H), 7.21 (m, 1 H), 2.98 (s, 3 H); MS (ES) m/z: 262 (M+H⁺).

To a solution of 72a (125 mg, 0.478 mmol) in anhydrous DMF (7 mL) wasadded NaH (1 eq, 60% dispersion in oil) under N₂. After stirring 10minutes, the bromide (3 eq) was added and the reaction mixture wasstirred at room temperature for 20 minutes. Water was added and thesolution was extracted with EtOAc (3 times). The organic layers werecombined, dried and concentrated. The product was purified by columnchromatography to give 72b (127 mg, 76%) as a yellow solid. ¹H NMR (300MHz, CDCl₃) δ 8.50 (dd, J=8.1, 1.5 Hz, 1 H), 8.44 (dd, J=4.7, 1.5 Hz, 1H), 8.14 (s, 1 H), 7.32–7.28 (m, 5 H), 7.26–7.21 (m, 1 H), 5.58 (s, 2H), 3.14 (s, 3 H); MS (ES) m/z: 352 (M+H⁺).

Compound 72b (51 mg, 0.145 mmol), Pd₂(dba)₃ (0.1 eq), organo-tincompound (1.5 eq) and P(^(t)Bu)₃ (0.6 eq) was mixed in anhydrous THF andDMF (10:1 by volume). The mixture was sealed in a tube and microwavedfor 350 seconds at 200° C. After concentration, the product was purifiedby column chromatography to give 72c (47 mg, 71%). ¹H NMR (300 MHz,CDCl₃) δ 8.49 (s, 1 H), 8.32 (dd, J=4.7, 1.5 Hz, 1 H), 8.02 (s, 1 H),7.32–7.29 (m, 5 H), 7.09 (dd, J=8.0, 1.5 Hz, 1 H), 6.93–6.89 (m, 1 H),5.55 (s, 2 H), 4.04 (s, 3 H), 3.34 (s, 3 H), 3.14 (s, 3 H); MS (ES) m/z:456 (M+H⁺).

To a solution of 72c (47 mg, 0.1 mmol) in EtOH (2 mL) was added KOHaqueous solution (10 N, ˜70 eq) and the reaction was stirred for 2hours. Water (5 mL) was added and the mixture was acidified with 10%citric acid. After extraction with CH₂Cl₂ (3 times), the organic layerswere dried and concentrated to give the crude product (46 mg).

To the above intermediate (46 mg) in anhydrous DMF (1.5 mL) was addedHMDS (10 eq) in 0.8 mL MeOH. The reaction was heated at 80° C. for 2hours then cooled slowly. After concentration, the product was purifiedby column chromatography to give 72 (12 mg, 26% for two steps). ¹H NMR(300 MHz, CDCl₃) δ 8.50 (s, 1 H), 8.33 (dd, J=4.7, 1.5 Hz, 1 H), 8.02(s, 1 H), 7.46 (s, 1 H), 7.33–7.29 (m, 5 H), 7.09 (dd, J=8.0, 1.5 Hz, 1H), 6.94–6.90 (m, 1 H), 5.56 (s, 2 H), 4.04 (s, 3 H), 3.34 (s, 3 H); MS(ES) m/z: 442 (M+H⁺).

EXAMPLE 573-(2,4-Dimethoxy-pyrimidin-5-yl)-4-(1-phenethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrrole-2,5-dione(Compound 73)

To a solution of 72a (250 mg, 0.96 mmol) in anhydrous DMF (15 mL) wasadded NaH (5 eq, 60% dispersion in oil) under N₂. After stirring 10minutes, the bromide (2 eq) was added and the reaction mixture washeated at 70° C. for 90 minutes. Water (15 mL) was added at 20° C.followed by EtOAc (50 mL). The aqueous layer was acidified with 1 N HClthen extracted with EtOAc (3 times). The organic layers were combined,dried and concentrated. The product was purified by columnchromatography to give 73a (37 mg, 11%). ¹H NMR (300 MHz, CDCl₃) δ 8.51(dd, J=8.1, 1.5 Hz, 1 H), 8.43 (dd, J=4.7, 1.5 Hz, 1 H), 7.90 (s, 1 H),7.26–7.20 (m, 3 H), 7.14–7.06 (m, 3 H), 4.62 (t, J=7.2 Hz, 2 H), 3.22(t, J=7.2 Hz, 2 H), 3.14 (s, 3 H); MS (ES) m/z: 366 (M+H⁺).

Compound 73a (38 mg, 0.1 mmol), Pd₂(dba)₃ (0.1 eq), organo-tin compound(1.5 eq) and P(^(t)Bu)₃ (0.6 eq) were mixed in anhydrous THF and DMF(10:1 by volume). The mixture was sealed in a tube and microwaved for350 seconds at 200° C. After concentration, the product was purified bycolumn chromatography to give 73b (27 mg, 55%). ¹H NMR (300 MHz, CDCl₃)δ 8.46 (s, 1 H), 8.31 (dd, J=4.7, 1.5 Hz, 1 H), 7.91 (s, 1 H), 7.31–7.23(m, 3 H), 7.18–7.15 (m, 2 H), 7.01 (dd, J=8.0, 1.5 Hz, 1 H), 6.91–6.87(m, 1 H), 4.62 (t, J=7.3 Hz, 2 H), 4.07 (s, 3 H), 3.44 (s, 3 H), 3.24(t, J=7.1 Hz, 2 H); MS (ES) m/z: 470 (M+H⁺).

To a solution of 73b (27 mg, 0.058 mmol) in EtOH (2 mL) was added KOHaqueous solution (10 N, ˜70 eq) and the reaction was stirred for 2hours. Water (5 mL) was added and the mixture was acidified with 10%citric acid. After extraction with CH₂Cl₂ (3 times), the organic layerswere dried and concentrated to give the crude product (23 mg).

To the above intermediate (23 mg) in anhydrous DMF (1.5 mL) was addedHMDS (10 eq) in 0.8 mL MeOH. The reaction was heated at 80° C. for 2hours then cooled slowly. The solvent was removed and the residue waspurified by column chromatography to give product 73 (9.2 mg, 35% forboth steps). ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1 H), 8.35 (dd, J=4.7,1.5 Hz, 1 H), 7.98 (s, 1 H), 7.28–7.23 (m, 3 H), 7.14–7.12 (m, 2 H),6.99–6.95 (m, 2 H), 4.64 (t, J=7.2 Hz, 2 H), 4.05 (s, 3 H), 3.41 (s, 3H), 3.24 (t, J=7.2 Hz, 2 H); MS (ES) m/z: 456 (M+H⁺).

EXAMPLE 583-(2,4-Dimethoxy-pyrimidin-5-yl)-4-[1-(3-thiophen-2-yl-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 74)

To a solution of 72a (50 mg, 0.19 mmol) in anhydrous CH₃CN (5 mL) wasadded K₂CO₃ (4 eq) under N₂. The reaction mixture turned red. Afterstirring 10 minutes the bromide (2 eq) was added and the reactionmixture was heated at 70° C. for 3 hours. Water was added at 20° C. andthe solution was extracted with EtOAc (3 times). The organic layers werecombined, dried and concentrated. The product was purified by columnchromatography to give 74a (25 mg, 34%) as a yellow solid. ¹H NMR (300MHz, CDCl₃) δ 8.50 (dd, J=8.1, 1.3 Hz, 1 H), 8.42 (d, J=4.4 Hz, 1 H),8.16 (s, 1 H), 7.22–7.20 (m, 1 H), 7.14 (dd, J=5.1, 1.0 Hz, 1 H), 6.93(m, 1 H), 6.84 (s, 1 H), 4.44 (t, J=7.0 Hz, 2 H), 3.16 (s, 3 H), 2.91(t, J=7.4 Hz, 2 H), 2.35 (m, 2 H); MS (ES) m/z: 386 (M+H⁺).

Compound 74a (39 mg, 0.1 mmol), Pd₂(dba)₃ (0.1 eq), organo-tin compound(1.5 eq) and P(^(t)Bu)₃ (0.6 eq) were mixed in anhydrous THF and DMF(10:1 by volume). The mixture was sealed in a tube and microwaved for350 seconds at 200° C. After cooling down and concentration, the productwas purified by column chromatography to give 74b (28 mg, 57%). ¹H NMR(300 MHz, CDCl₃) δ 8.49 (s, 1 H), 8.42 (dd, J=8.1, 1.3 Hz, 1 H), 8.29(d, J=4.4 Hz, 1 H), 8.09 (s, 1 H), 7.18–7.13 (m, 1 H), 7.07 (dd, J=5.1,1.0 Hz, 1 H), 6.92 (m, 1 H), 6.84 (s, 1 H), 4.42 (t, J=7.0 Hz, 2 H),4.04 (s, 3 H), 3.44 (s, 3 H), 3.17 (s, 3 H), 2.89 (t, J=7.4 Hz, 2 H),2.33 (m, 2 H); MS (ES) m/z: 490 (M+H⁺).

To a solution of 74b (25 mg, 0.05 mmol) in EtOH (2 mL) was added KOHaqueous solution (10 N, ˜70 eq) and the reaction was stirred for 2hours. Water (5 mL) was added and the mixture was acidified with 10%citric acid. After extraction with CH₂Cl₂ (3 times), the organic layerswere dried and concentrated to give the crude product (24 mg).

To the above intermediate (24 mg) in anhydrous DMF (1.5 mL) was addedHMDS (10 eq) in 0.8 mL MeOH. The reaction was heated at 80° C. for 2hours then cooled down slowly. The solvent was removed and the residuewas purified by flash column to give product 74 (6 mg, 25% for bothsteps). ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1 H), 8.42 (dd, J=8.1, 1.3Hz, 1 H), 8.31 (d, J=4.4 Hz, 1 H), 8.11 (s, 1 H), 7.18–7.16 (m, 1 H),7.07 (dd, J=7.8, 1.5 Hz, 1 H), 6.95 (m, 1 H), 6.86 (s, 1 H), 4.44 (t,J=7.0 Hz, 2 H), 4.06 (s, 3 H), 3.46 (s, 3 H), 2.91 (t, J=7.6 Hz, 2 H),2.36 (m, 2 H); MS (ES) m/z: 476 (M+H⁺).

EXAMPLE 593-(2,4-Dimethoxy-pyrimidin-5-yl)-4-{1-[2-(4-fluoro-phenoxy)-ethyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dione(Compound 75)

To a solution of 72a (50 mg, 0.19 mmol) in anhydrous CH₃CN (5 mL) wasadded K₂CO₃ (4 eq) under N₂. The reaction mixture turned red. Afterstirring 10 minutes the bromide (2 eq) was added and the reactionmixture was heated at 70° C. for 3 hours. Water was added at 20° C. andthe solution was extracted with EtOAc (3 times). The organic layers werecombined and dried. After concentration, the product was purified bycolumn chromatography to give 75a (26 mg, 34%) as a yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 8.49 (dd, J=8.1 Hz, 1.5 Hz, 1 H), 8.40 (dd, J=4.7,1.5 Hz, 1 H), 8.35 (s, 1 H), 7.24–7.20 (m, 1 H), 6.98–6.95 (m, 2 H),6.94–6.90 (m, 2 H), 4.77 (t, J=5.0 Hz, 2 H), 4.33 (t, J=5.0 Hz, 2 H),3.16 (s, 3 H); MS (ES) m/z: 400 (M+H⁺).

Compound 75a (50 mg, 0.125 mmol), Pd₂(dba)₃ (0.1 eq), organo-tincompound (1.5 eq) and P(^(t)Bu)₃ (0.6 eq) were mixed in anhydrous THFand DMF (10:1 by volume). The mixture was sealed in a tube andmicrowaved for 350 seconds at 200° C. After concentration, the residuewas purified by flash chromatography to get pure product 75b (20 mg,32%). ¹H NMR (300 MHz, CDCl₃) δ 8.50 (s, 1 H), 8.30 (dd, J=4.7, 1.5 Hz,1 H), 8.24 (s, 1 H), 7.10 (dd, J=7.9, 1.5 Hz, 1 H), 6.99–6.90 (m, 3 H),6.86–6.82 (m, 2 H), 4.77 (t, J=5.1 Hz, 2 H), 4.35 (t, J=5.0 Hz, 2 H),4.05 (s, 3 H), 3.38 (s, 3 H), 3.20 (s, 3 H); MS (ES) m/z: 504 (M+H⁺).

To a solution of 75b (20 mg, 0.04 mmol) in EtOH (2 mL) was added KOHaqueous solution (10 N, ˜70 eq) and the reaction was stirred for 2hours. Water (5 mL) was added and the mixture was acidified with 10%citric acid. After extraction with CH₂Cl₂ (3 times), the organic layerswere dried and concentrated to give the crude product (19 mg).

To the above intermediate (19 mg) in anhydrous DMF (1.5 mL) was addedHMDS (10 eq) in 0.8 mL MeOH. The reaction was heated at 80° C. for 2hours then cooled slowly. The solvent was removed and the residue waspurified by column chromatography to get product 75 (5 mg, 26% for bothsteps). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1 H), 8.30 (dd, J=4.7, 1.5Hz, 1 H), 8.24 (s, 1 H), 7.10 (dd, J=7.9, 1.5 Hz, 1 H), 6.96–6.93 (m, 3H), 6.87–6.83 (m, 2 H), 4.77 (t, J=5.1 Hz, 2 H), 4.36 (t, J=5.0 Hz, 2H), 4.05 (s, 3 H), 3.38 (s, 3 H), 3.20 (s, 3 H); MS (ES) m/z: 490(M+H⁺).

EXAMPLE 603-(2,4-Dimethoxy-pyrimidin-5-yl)-4-[1-(3-phenoxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione(Compound 76)

To a solution of 65c (30 mg, 0.079 mmol) and Pd(^(t)Bu₃P)₂ (0.1 eq) inTHF (3 mL) was added the stannane derivative (2 eq) at 23° C. undernitrogen. The reaction mixture was refluxed for 18 h. Upon cooling, themixture was diluted with EtOAc (10 mL) and washed with H₂O, KF, brineand dried. After concentration, the crude product was purified by columnchromatography (SiO₂) to give Compound 76 (9 mg, 23%). MS (ES) m/z: 486(M+H⁺).

EXAMPLE 61N-[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]-acetamide(Compound 77)

A mixture of compound 38 (TFA salt) (577.8 mg, 0.95 mmol) in pyridinewas cooled to 0° C., to which was added dropwise acetyl chloride (90 mg,1.14 mmol). The mixture was stirred at 0° C. for 10 min, and then roomtemperature for 1 h. The reaction was quenched with sat'd NaHCO₃,extracted several times with EtOAc. The orgaic layers were combined,dried (Na₂SO₄) and concentrated to give the crude product, which waspurified by flash chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from99:1:0.1 to 97:3:0.3) to give 134 mg of Compound 77 as a yellow solid.Compound 77 was converted to its mesylate salt. ¹H NMR (CD₃OD) δ 8.34(m, 1 H), 8.22 (s, 1 H), 7.45 (m, 1 H), 7.39 (m, 1 H), 7.30 (m, 1 H),7.06 (m, 3 H), 4.44 (t, J=6.9 Hz, 2 H), 3.42 (s, 3 H), 3.22 (t, J=6.7Hz, 2 H), 2.11 (m, 2 H), 1.96 (s, 3 H). ES-MS m/z 419 (MH⁺).

EXAMPLE 62N-[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]-formamide(Compound 78)

To a mixture of compound 38 (48.3 mg, 0.128 mmol) in DMF was addedexcess of butyl formate. The mixture was heated at 80° C. for 5 h. Thesolvent was evaporated and the residue was extracted with EtOAc. Theorganic layers were combined, washed with H₂O and brine, dried (Na₂SO₄)and concentrated to give the crude 78, which was then purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 99:1:0.1 to97:3:0.3) to give 31 mg of Compound 78 as a yellow solid. ¹H NMR (CDCl₃)δ 8.27 (s, 1H), 8.21 (dd, J=1.7, 4.5 Hz, 1 H), 8.12 (s, 1 H), 7.45 (m, 2H), 7.04 (t, J=7.4 Hz, 1 H), 6.87 (d, J=8.2 Hz, 1 H), 6.75 (m, 2 H),4.43 (t, J=2.4 Hz, 2 H), 3.38 (s, 3 H), 3.16 (dd, J=6.3, 12.2 Hz, 2 H),2.10 (dd, J=6.3, 12.3 Hz, 2 H). ES-MS m/z 405 (MH⁺).

EXAMPLE 63N-[3-[3-[2,5-dihydro-4-(2-methoxyphenyl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl]-formamide(Compound 79)

To a mixture of compound 38 (21.2 mg, 0.056 mmol) in THF was addedpyridine (13.3 mg, 0.168 mmol) and methanesufonic anhydride (19.6 mg,0.113 mmol). The mixture was heated at 50° C. for 3 h. The solvent wasevaporated and the residue was extracted with EtOAc. The organic layerswere combined, washed with H₂O and brine, dried (Na₂SO₄) andconcentrated to give the crude 79, which was then purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, from 99:1:0.1 to97:3:0.3) to give 11.5 mg of Compound 79 as a yellow solid. ¹H NMR(CD₃OD) δ 8.17 (m, 1 H), 8.15 (s, 1 H), 7.42 (t, J=7.9 Hz, 1 H), 7.33(d, J=7.5 Hz, 1 H), 6.98 (t, J=8.9 Hz, 2 H), 6.76 (m, 2 H), 4.44 (t,J=6.8 Hz, 2 H), 3.36 (s, 3 H), 3.08 (t, J=6.7 Hz, 2 H), 2.91 (s, 3 H),2.12 (m, 2 H). ES-MS m/z 455 (MH⁺).

EXAMPLE 64

As a specific embodiment of an oral composition, 100 mg of Compound 4prepared according to Example 4 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

Biological Experimental Examples

The utility of the compounds to treat kinase or dual-kinase mediateddisorders (in particular, kinases selected from glycogen synthasekinase-3 and protein kinase C; and, more particularly, kinases selectedfrom glycogen synthase kinase-3β, protein kinase C α, protein kinase Cβ-II, or protein kinase C γ) was determined using the followingprocedures.

Glycogen Synthase Kinase-3 Assay

Compounds were tested for the ability to inhibit recombinant rabbitGSK-3β protein using the following protocol. The test compound was addedto a reaction mixture containing Protein Phosphatase Inhibitor-2 (PPI-2)(Calbiochem) (45 ng), rabbit GSK-3β protein (New England Biolabs) (0.75units) and ³³P-ATP (1 μCi) in 50 mM Tris-HCl (pH 8.0), 10 mM MgCl₂, 0.1%BSA, 1 mM DTT and 100 μM Sodium Vanadate. The mixture was reacted for 90minutes at 30° C. to allow phosphorylation of the PPI-2 protein and thenthe protein in the reaction was precipitated using 10% TCA. Theprecipitated protein was collected on filter plates(MultiScreen-DV/Millipore), which were subsequently washed. Finally, theradioactivity was quantified using a TopCount Scintillation Counter(Packard). GSK-3 inhibitory compounds resulted in less phosphorylatedPPI-2 and thus a lower radioactive signal in the precipitated protein.Staurosporine or Valproate, known inhibitors of GSK-3β, were used as apositive control for screening.

Protein Kinase C Histone-Based Assay

Compounds were evaluated for PKC isozyme selectivity using histone IIIas the substrate. PKC isozymes α, β-II or γ were added to a reactionmixture that contained 20 mM HEPES, (pH 7.4), 940 μM CaCl₂, 10 mM MgCl₂,1 mM EGTA. 100 μg/mL phosphatidylserine, 20 μg/mL diacylglycerol, 30 μMATP, 1 μCi [³³P]ATP and 200 μg/mL histone III. The reaction wasincubated for 10 min at 30° C. Reactions were terminated by TCAprecipitation and spotting on Whatman P81 filters. Filters were washedin 75 mM phosphoric acid and the radioactivity quantified by liquidscintillation counting.

Table 2 shows the biological activity in the GSK-3β and PKC (histone)assays as an IC₅₀ value (μM) or in % inhibition (data obtained ondifferent days when two numbers are present) for representativecompounds of the present invention.

TABLE 2 Biological Activity (IC₅₀ μM, or % inhibition) Cpd GSK-3β PKC-αPKC-βII PKC-γ 1 0.009/0.010 18% @1 μM 14% @1 μM 48% @1 μM  2% @10 μM 81%@10 μM 43% @10 μM 2 0.019  0% @1 μM 22% @1 μM 46% @1 μM  1% @10 μM 50%@10 μM 54% @10 μM 3 0.030/0.031  0% @1 μM 30% @1 μM 20% @1 μM 51% @10 μM89% @10 μM 31% @10 μM 4 51% @100 nM  0% @1 μM 47% @1 μM 48% @1 μM 34%@10 μM 84% @10 μM 59% @10 μM 5 56% @400 nM  0% @1 μM 21% @1 μM 44% @1 μM34% @10 μM 81% @10 μM 57% @10 μM 6 56% @100 nM 7 0.051 8 0.003 9 0.01110 0.010 11 0.004 13 0.036 14 0.006 15 0.006 16 0.1 17 19% @100 nM 1829% @200 nM 19 25% @200 nM 20 21% @1 μM 0.053 0.002 0.151 21 44% @1 μM1.44 0.036 0.859 22 0.33 23 0.158/0.051 24 0.015/0.008 25 0.071/0.044 260.07/0.12 30 0.04/0.05 32 0.067/0.095 34 0.005/0.009 0.452 39% @1 μM 43%@1 μM 35 0.008/0.011 31% @10 μM 35% @1 μM 35% @10 μM 36 0.067/0.067 370.014/0.019 5.27 0.342 4.75 38 0.031/0.043 32% @1 μM 26% @1 μM 24% @1 μM39 0.023/0.016 41% @10 μM 52% @1 μM 41% @10 μM 40 0.009/0.015 410.037/0.042 42 0.123/0.106 43 0.198/0.126 44 32% @1 μM/ 25% @1 μM 450.028/0.018 46 0.038/0.037 47 0.046/0.054 48 0.047/0.038 49 0.056/0.05850 0.088/0.107 51 0.150/0.187 52 0.179/0.212 53 0.211/0.143 540.232/0.161 55  4% @1 μM/ 13% @1 μM 56 23% @1 μM/ 20% @1 μM 570.015/0.010 58 0.366/0.344 59 0.519/0.424 60 0.625 61 0.714/0.635 620.036/0.035 63 0.077/0.102 64 0.077/0.128 65 0.188/0.244 66 0.48/0.66 670.140/0.059 68 43% @1 μM/ 40% @1 μM 69 0.1 70 0.38 71 0.36 72 54% @1 μM73 0.1 74 39% @1 μM 75 0.24 76 0.043/0.059 77 0.002/0.003 26% @10 μM 49%@1 μM 78 0.007/0.009 33% @10 μM 21% @1 μM 48% @10 μM

The results from the foregoing indicate that a compound of the presentinvention would be expected to be useful in treating or ameliorating akinase or dual-kinase mediated disorder.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I):

wherein R is a 6-membered heterocyclyl; R¹ is selected from the groupconsisting of hydrogen, —C₁₋₈alkyl-R⁵, —C₂₋₈alkenyl-R⁵, —C₂₋₈alkynyl-R⁵,—C(O)—(C₁₋₈)alkyl-R⁹, —C(O)-aryl-R⁸, —C(O)—O—(C₁₋₈)alkyl-R⁹,—C(O)—O-aryl-R⁸, —C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—NH(aryl-R⁸),—C(O)—N(C₁₋₈alkyl-R⁹)₂, —SO₂—(C₁₋₈)alkyl-R⁹, —SO₂-aryl-R⁸,-cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and -heteroaryl-R⁶; whereinheterocyclyl and heteroaryl are attached to the azaindole nitrogen atomin the one position via a heterocyclyl or heteroaryl ring carbon atom;R² is one substituent attached to a carbon or nitrogen atom selectedfrom the group consisting of hydrogen, —C₁₋₈alkyl-R⁵, —C₂₋₈alkenyl-R⁵,—C₁₋₈alkynyl-R⁵, —C(O)H, —C(O)—(C₁₋₈)alkyl-R⁹, —C(O)—NH₂,—C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—N(C₁₋₈alkyl-R⁹)₂, —C(O)—NH(aryl-R⁸),—C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸,—C(O)-heteroaryl-R⁸, —CO₂H, —C(O)—O—(C₁₋₈)alkyl-R⁹, —C(O)—O-aryl-R⁸,—SO₂—(C₁₋₈)alkyl-R⁹, —SO₂-aryl-R⁸, -cycloalkyl-R⁶, -aryl-R⁶ and—(C₁₋₈)alkyl-N—R⁷; with the proviso that, when R² is attached to acarbon atom, R² is further selected from the group consisting of—C₁₋₈alkoxy-R⁵, —N—R⁷, cyano, halogen, hydroxy, nitro, oxo,-heterocyclyl-R⁶ and -heteroaryl-R⁶; R³ is 1 to 3 substituents attachedto a carbon atom independently selected from the group consisting ofhydrogen, —C₁₋₈alkyl-R¹⁰, —C₂₋₈alkenyl-R¹⁰, —C₂₋₈alkynyl-R¹⁰,—C₁₋₈alkoxy-R¹⁰, —C(O)H, —C(O)—(C₁₋₈)alkyl-R⁹, —C(O)—NH₂,—C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—N(C₁₋₈alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸,—C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂,—CO₂H, —C(O)—O—(C₁₋₈)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂-(C₁₋₈)alkyl-R⁹,—SO₂-aryl-R⁸, —N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸,-heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁸; R⁴ is 1 to 4 substituentsattached to a carbon atom independently selected from the groupconsisting of hydrogen, —C₁₋₈alkyl-R¹⁰, —C₂₋₈alkenyl-R¹⁰,—C₂₋₈alkynyl-R¹⁰, —C₁₋₈alkoxy-R¹⁰, —C(O)H, —C(O)—(C₁₋₈)alkyl-R⁹,—C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl-R⁹), —C(O)—N(C₁₋₈alkyl-R⁹)₂,—C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸,—C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H, —C(O)—O—(C₁₋₈)alkyl-R⁹,—C(O)—O-aryl-R⁸, —SH, —S—(C₁₋₈)alkyl-R¹⁰, —SO₂—(C₁₋₈)alkyl-R⁹,—SO₂-aryl-R⁸, —SO₂—NH₂, —SO₂—NH(C₁₋₈alkyl-R⁹), —SO₂—N(C₁₋₈alkyl-R⁹)₂,—N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁸,-aryl-R⁸ and -heteroaryl-R⁸; R⁵ is 1 to 2 substituents independentlyselected from the group consisting of hydrogen, —O—(C₁₋₈)alkyl,—O-aryl-R⁶, —O—(C₁₋₈)alkyl-OH, —O—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl,—O—(C₁₋₈)alkyl-NH₂, —O—(C₁₋₈)alkyl-NH(C₁₋₈alkyl),—O—(C₁₋₈)alkyl-N(C₁₋₈)alkyl)₂, —O—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl,—O—(C₁₋₈)alkyl-SO₂—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—NH₂,—O—(C₁₋₈)alkyl-SO₂—NH(C₁₋₈alkyl), —O—(C₁₋₈)alkyl-SO₂—N(C₁₋₈alkyl)₂,—O—C(O)H, —O—C(O)—(C₁₋₈)alkyl, —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₈alkyl),—O—C(O)—N(C₁₋₈alkyl)₂, —O—(C₁₋₈)alkyl-C(O)H,—O—(C₁₋₈)alkyl-C(O)—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-CO₂H,—O—(C₁₋₈)alkyl-C(O)—O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-C(O)—NH₂,—O—(C₁₋₈)alkyl-C(O)—NH(C₁₋₈alkyl), —O—(C₁₋₈)alkyl-C(O)—N(C₁₋₈alkyl)₂,—C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,—C(NH)—NH₂, —C(O)—NH(C₁₋₈alkyl), —C(O)—N(C₁₋₈alkyl)₂, —SH,—S—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-OH,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH₂,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH(C₁₋₈alkyl),—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-N(C₁₋₈alkyl)₂,—S—(C₁₋₈)alkyl-NH(C₁₋₈alkyl), —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,—SO₂—NH(C₁₋₈alkyl), —SO₂—N(C₁₋₈alkyl)₂, —N—R⁷, cyano, (halo)₁₋₃,hydroxy, nitro, oxo, -cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and-heteroaryl-R⁶; R⁶ is 1 to 4 substituents attached to a carbon ornitrogen atom independently selected from the group consisting ofhydrogen, —C₁₋₈alkyl, —C₂₋₈alkenyl, —C₂₋₈alkynyl, —C(O)H,—C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂,—C(O)—NH(C₁₋₈alkyl), —C(O)—N(C₁₋₈)alkyl)₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,—SO₂—NH(C₁₋₈alkyl), —SO₂—N(C₁₋₈alkyl)₂, —(C₁₋₈)alkyl-N—R⁷,—(C₁₋₈)alkyl-(halo)₁₋₃, —(C₁₋₈)alkyl-OH, -aryl-R⁸, —(C₁₋₈)alkyl-aryl-R⁸and —(C₁₋₈)alkyl-heteroaryl-R⁸; with the proviso that, when R⁶ isattached to a carbon atom, R⁶ is further selected from the groupconsisting of —C₁₋₈alkoxy, —(C₁₋₈)alkoxy-(halo)₁₋₃, —SH, —S—(C₁₋₈)alkyl,—N—R⁷, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R⁸; R⁷ is 2substituents independently selected from the group consisting ofhydrogen, —C₁₋₈alkyl, —C₂₋₈alkenyl, —C₂₋₈alkynyl, —(C₁₋₈)alkyl-OH,—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-NH₂,—(C₁₋₈)alkyl-NH(C₁₋₈alkyl), —(C₁₋₈)alkyl-N(C₁₋₈alkyl)₂,—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —C(O)H, —C(O)—(C₁₋₈)alkyl,—C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₈alkyl),—C(O)—N(C₁₋₈alkyl)₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₈alkyl),—SO₂—N(C₁₋₈alkyl)₂, —C(N)—NH₂, -cycloalkyl-R⁸,—(C₁₋₈)alkyl-heterocyclyl-R⁸, -aryl-R⁸, —(C₁₋₈)alkyl-aryl-R⁸ and—(C₁₋₈)alkyl-heteroaryl-R⁸; R⁸ is 1 to 4 substituents attached to acarbon or nitrogen atom independently selected from the group consistingof hydrogen, —C₁₋₈alkyl, —(C₁₋₈)alkyl-(halo)₁₋₃ and —(C₁₋₈)alkyl-OH;with the proviso that, when R⁸ is attached to a carbon atom, R⁸ isfurther selected from the group consisting of —C₁₋₈alkoxy, —NH₂,—NH(C₁₋₈alkyl), —N(C₁₋₈alkyl)₂, cyano, halo, —(C₁₋₈)alkoxy-(halo)₁₋₃,hydroxy and nitro; R⁹ is 1 to 2 substituents independently selected fromthe group consisting of hydrogen, —C₁₋₈alkoxy, —NH₂, —NH(C₁₋₈alkyl),—N(C₁₋₈alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro; R¹⁰ is 1 to 2substituents independently selected from the group consisting ofhydrogen, —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈alkyl)₂, cyano, (halo)₁₋₃,hydroxy, nitro and oxo; and Y and Z is each O; and pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1 wherein R⁵ is 1 to2 substituents independently selected from the group consisting ofhydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶, —O—(C₁₋₄)alkyl-OH,—O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-NH₂,—O—(C₁₋₄)alkyl-NH(C₁₋₄alkyl), —O—(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂,—O—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-SO₂—NH₂, —O—(C₁₋₄)alkyl-SO₂—NH(C₁₋₄alkyl),—O—(C₁₋₄)alkyl-SO₂—N(C₁₋₄alkyl)₂, —O—C(O)H, —O—C(O)—(C₁₋₄)alkyl,—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₄alkyl), —O—C(O)—N(C₁₋₄alkyl)₂,—O—(C₁₋₄)alkyl-C(O)H, —O—(C₁₋₄)alkyl-C(O)—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-CO₂H, —O—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-C(O)—NH₂, —O—(C₁₋₄)alkyl-C(O)—NH(C₁₋₄alkyl),—O—(C₁₋₄)alkyl-C(O)—N(C₁₋₄alkyl)₂, —C(O)H, —C(O)—(C₁₋₄)alkyl, —CO₂H,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄alkyl)₂, —SH, —S—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-OH,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH₂,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH(C₁₋₄alkyl),—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂,—S—(C₁₋₄)alkyl-NH(C₁₋₄alkyl), —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH(C₁₋₄alkyl), —SO₂—N(C₁₋₄alkyl)₂, —N—R⁷, cyano, (halo)₁₋₃,hydroxy, nitro, oxo, -cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and-heteroaryl-R⁶.
 3. The compound of claim 1 wherein R⁵ is 1 to 2substituents independently selected from the group consisting ofhydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶, —N—R⁷, hydroxy, and-heteroaryl-R⁶.
 4. The compound of claim 1 wherein R⁵ is 1 to 2substituents independently selected from the group consisting ofhydrogen, —O—(C₁₋₄)alkyl, —O-aryl-R⁶, —N—R⁷, hydroxy, -imidazolyl-R⁶,-triazolyl-R⁶, and -tetrazolyl-R⁶.
 5. The compound of claim 1 wherein R⁶is 1 to 4 substituents attached to a carbon or nitrogen atomindependently selected from the group consisting of hydrogen,—C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C(O)H, —C(O)—(C₁₋₄)alkyl,—CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄)alkyl)₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl),—SO₂—N(C₁₋₄alkyl)₂, —(C₁₋₄)alkyl-N—R⁷, —(C₁₋₄)alkyl-(halo)₁₋₃,—(C₁₋₄)alkyl-OH, -aryl-R⁸, —(C₁₋₄)alkyl-aryl-R⁸ and—(C₁₋₄)alkyl-heteroaryl-R⁸; with the proviso that, when R⁶ is attachedto a carbon atom, R⁶ is further selected from the group consisting of—C₁₋₄alkoxy, —(C₁₋₄)alkoxy-(halo)₁₋₃, —SH, —S—(C₁₋₄)alkyl, —N—R⁷, cyano,halo, hydroxy, nitro, oxo and -heteroaryl-R⁸.
 6. The compound of claim 1wherein R⁷ is 2 substituents independently selected from the groupconsisting of hydrogen, —C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-NH₂,—(C₁₋₄)alkyl-NH(C₁₋₄alkyl), —(C₁₋₄)alkyl-N(C₁₋₄alkyl)₂,—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —C(O)H, —C(O)—(C₁₋₄)alkyl,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄alkyl)₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl),—SO₂—N(C₁₋₄alkyl)₂, —C(N)—NH₂, -cycloalkyl-R⁸,—(C₁₋₄)alkyl-heterocyclyl-R⁸, -aryl-R⁸, —(C₁₋₄)alkyl-aryl-R⁸, and—(C₁₋₄)alkyl-heteroaryl-R⁸.
 7. The compound of claim 1 wherein R⁷ is 2substituents independently selected from the group consisting of ofhydrogen, —C₁₋₄alkyl, —C(O)H, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl,—SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl), and —SO₂—N(C₁₋₄alkyl)₂.
 8. The compound ofclaim 1 wherein R⁸ is 1 to 4 substituents attached to a carbon ornitrogen atom independently selected from the group consisting ofhydrogen, —C₁₋₄alkyl, —(C₁₋₄)alkyl-(halo)₁₋₃, and —(C₁₋₄)alkyl-OH; withthe proviso that, when R⁸ is attached to a carbon atom, R⁸ is furtherselected from the group consisting of —C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, cyano, halo, —(C₁₋₄)alkoxy-(halo)₁₋₃, hydroxy, andnitro.
 9. The compound of claim 1 wherein R⁹ is 1 to 2 substituentsindependently selected from the group consisting of hydrogen,—C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, (halo)₁₋₃,hydroxy, and nitro.
 10. The compound of claim 1 wherein R⁶, R⁸, and R⁹are hydrogen.
 11. The compound of claim 1 wherein R² is one substituentattached to a carbon or nitrogen atom selected from the group consistingof hydrogen, —C₁₋₄alkyl-R⁵, —C₂₋₄alkenyl-R⁵, —C₂₋₄alkynyl-R⁵, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl-R⁹),—C(O)—N(C₁₋₄alkyl-R⁹)₂, —C(O)—NH(aryl-R⁸), —C(O)-cycloalkyl-R⁸,—C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₄)alkyl-R⁹,—SO₂-aryl-R⁸, -cycloalkyl-R⁶, -aryl-R⁶ and —(C₁₋₄)alkyl-N—R⁷; with theproviso that, when R² is attached to a carbon atom, R² is furtherselected from the group consisting of —C₁₋₄alkoxy-R⁵, —N—R⁷, cyano,halogen, hydroxy, nitro, oxo, -heterocyclyl-R⁶ and -heteroaryl-R⁶. 12.The compound of claim 1 wherein R² is one substituent attached to acarbon or nitrogen atom selected from the group consisting of hydrogen,—C₁₋₄alkyl-R⁵, —C₂₋₄alkenyl-R⁵, —C₂₋₄alkynyl-R⁵, —CO₂H,—C(O)—O—(C₁₋₄)alkyl-R⁹, -cycloalkyl-R⁶, -alkyl-R⁶ and —(C₁₋₄)alkyl-N—R⁷;with the proviso that, when R² is attached to a nitrogen atom, aquaternium salt is not formed; and, with the proviso that, when R² isattached to a carbon atom, R² is further selected from the groupconsisting of —C₁₋₄alkoxy-R⁵, —N—R⁷, cyano, halogen, hydroxy, nitro,oxo, -heterocyclyl-R⁶ and -heteroaryl-R⁶.
 13. The compound of claim 1wherein R² is one substituent attached to a carbon or nitrogen atomselected from the group consisting of hydrogen, —C₁₋₄alkyl-R⁵ and-aryl-R⁶; with the proviso that when R² is attached to a nitrogen atom,a quaternium salt is not formed; and, with the proviso that when R² isattached to a carbon atom, R² is further selected from the groupconsisting of —N—R⁷, halogen, hydroxy and -heteroaryl-R⁶.
 14. Thecompound of claim 1 wherein R³ is 1 to 3 substituents attached to acarbon atom independently selected from the group consisting ofhydrogen, —C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰,—C₁₋₄alkoxy-R¹⁰, —C(O)H, —C(O)—(C₁₋₄)alkyl-R⁹, —C(O)—NH₂,—C(O)—NH(C₁₋₄alkyl-R⁹), —C(O)—N(C₁₋₄alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸,—C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸, —C(O)-heteroaryl-R⁸, —C(NH)—NH₂,—CO₂H, —C(O)—O—(C₁₋₄)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C₁₋₈)alkyl-R⁹,—SO₂-aryl-R⁸, —N—R⁷, —(C₁₋₄)alkyl-N—R⁷, cyano, halogen, hydroxy, nitro,-cycloalkyl-R⁸, -heterocyclyl-R⁸, -aryl-R⁸ and -heteroaryl-R⁸.
 15. Thecompound of claim 1 wherein R³ is one substituent attached to a carbonatom selected from the group consisting of hydrogen, —C₁₋₄alkyl-R¹⁰,—C₂₋₄alkenyl-R¹⁰, —C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰, —C(O)H, —CO₂H,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, cyano, halogen, hydroxy, andnitro.
 16. The compound of claim 1 wherein R³ is one substituentattached to a carbon atom selected from the group consisting ofhydrogen, —C₁₋₄alkyl-R¹⁰, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, halogen,and hydroxy.
 17. The compound of claim 1 wherein R⁴ is 1 to 4substituents attached to a carbon atom independently selected from thegroup consisting of hydrogen, —C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰,—C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰, —C(O)H, —C(O)—(C₁₋₄)alkyl-R⁹,—C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl-R⁹), —C(O)—N(C₁₋₄alkyl-R⁹)₂,—C(O)-cycloalkyl-R⁸, —C(O)-heterocyclyl-R⁸, —C(O)-aryl-R⁸,—C(O)-heteroaryl-R⁸, —C(NH)—NH₂, —CO₂H, —C(O)—O—(C₁₋₄)alkyl-R⁹,—C(O)—O-aryl-R⁸, —SH, —S—(C₁₋₄)alkyl-R¹⁰, —SO₂—(C₁₋₄)alkyl-R⁹,—SO₂-aryl-R⁸, —SO₂—NH₂, —SO₂—NH(C₁₋₄alkyl-R⁹), —SO₂—N(C₁₋₄alkyl-R⁹)₂,—N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁸,-aryl-R⁸ and -heteroaryl-R⁸.
 18. The compound of claim 1 wherein R⁴ is 1to 4 substituents attached to a carbon atom independently selected fromthe group consisting of hydrogen, —C₁₋₄alkyl-R¹⁰, —C₂₋₄alkenyl-R¹⁰,—C₂₋₄alkynyl-R¹⁰, —C₁₋₄alkoxy-R¹⁰, —C(O)H, —CO₂H, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, cyano, halogen, hydroxy, nitro, -cycloalkyl,-heterocyclyl, -aryl and -heteroaryl.
 19. The compound of claim 1wherein R⁴ is 1 to 4 substituents attached to a carbon atomindependently selected from the group consisting of hydrogen,C₁₋₄alkyl-R¹⁰, C₁₋₄alkoxy-R¹⁰, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,halogen, and hydroxy.
 20. The compound of claim 1 wherein R⁴ is 1 to 4substituents attached to a carbon atom independently selected from thegroup consisting of hydrogen, C₁₋₄alkyl-R¹⁰, C₁₋₄alkoxy-R¹⁰, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, chlorine, fluorine, and hydroxy.
 21. Thecompound of claim 1 wherein R¹⁰ is 1 to 2 substituents independentlyselected from the group consisting of hydrogen, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, cyano, (halo)₁₋₃, hydroxy, nitro, and oxo.
 22. Thecompound of claim 1 wherein R¹⁰ is 1 to 2 substituents independentlyselected from the group consisting of hydrogen and (halo)₁₋₃.
 23. Thecompound of claim 1 wherein R¹⁰ is 1 to 2 substituents independentlyselected from the group consisting of hydrogen and (fluoro)₃.
 24. Thecompound of claim 1 wherein the compound of Formula (I) is a compoundselected from Formula (Ia):

wherein R, R¹, R², R³, and R⁴ are dependently selected from: R¹ R³ R R²R⁴ HO(CH₂)₃ H 2-pyridinyl H H; HO(CH₂)₃ H 2-pyridinyl H 3-Cl-5-CF₃;HO(CH₂)₃ H 3,4-dihydro-2H-pyran- H H; 6-yl HO(CH₂)₃ H pyrimidin-5-yl2-OMe 4-OMe HO(CH₂)₃ H pyrimidin-5-yl H H HO(CH₂)₃ H 2-oxo-2H-pyran-3-ylH H HO(CH₂)₃ H pyrazin-2-yl H H HO(CH₂)₃ H 5,6-dihydro- H H[1,4]dioxin-2-yl HO(CH₂)₃ H pyrimidin-2-yl H H Ph(CH₂)₃ H pyrimidin-5-yl2-MeO 4-MeO Ph(CH₂)₃ H pyrimidin-5-yl H H Ph(CH₂)₃ H pyrazin-2-yl H HPh(CH₂)₃ H 5,6-dihydro-4H- H H pyran-2-yl NC(CH₂)₃ H pyrimidin-5-yl2-Meo 4-MeO NC(CH₂)₃ H pyrazin-2-yl H H HO(CH₂)₃ H 1H-pyrimidine-2,4- HH dione-5-yl MeO(CH₂)₂ H pyrimidin-5-yl 2-MeO 4-MeO PhCH₂ Hpyrimidin-5-yl 2-MeO 4-MeO Ph(CH₂)₂ H pyrimidin-5-yl 2-MeO 4-MeO3-thiophen-2- H pyrimidin-5-yl 2-MeO 4-MeO yl-propyl 2-(4-fluoro- Hpyrimidin-5-yl 2-MeO 4-MeO phenoxy)-ethyl and PhO(CH₂)₃ H pyrimidin-5-yl2-MeO 4-MeO.


25. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 26. A method for preparing apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier.